Phosphoinositide 3-kinase inhibitor compounds and methods of use

ABSTRACT

Compounds of Formulas Ia and Ib, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula Ia and Ib for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

PRIORITY OF INVENTION

This application claims priority to U.S. Provisional Application No.60/795,047 that was filed on 26 Apr. 2006. The entire content of thisprovisional application is hereby incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates generally to compounds with anti-cancer activityand more specifically to compounds which inhibit PI3 kinase activity.The invention also relates to methods of using the compounds for invitro, in situ, and in vivo diagnosis or treatment of mammalian cells,or associated pathological conditions.

BACKGROUND OF THE INVENTION

Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of anumber of phospholipids found in cell membranes. In recent years it hasbecome clear that PI plays an important role in intracellular signaltransduction. Cell signaling via 3′-phosphorylated phosphoinositides hasbeen implicated in a variety of cellular processes, e.g., malignanttransformation, growth factor signaling, inflammation, and immunity(Rameh et al (1999) J. Biol Chem, 274:8347-8350). The enzyme responsiblefor generating these phosphorylated signaling products,phosphatidylinositol 3-kinase (also referred to as PI 3-kinase or PI3K),was originally identified as an activity associated with viraloncoproteins and growth factor receptor tyrosine kinases thatphosphorylate phosphatidylinositol (PI) and its phosphorylatedderivatives at the 3′-hydroxyl of the inositol ring (Panayotou et al(1992) Trends Cell Biol 2:358-60).

Phosphoinositide 3-kinases (PI3K) are lipid kinases that phosphorylatelipids at the 3-hydroxyl residue of an inositol ring (Whitman et al(1988) Nature, 332:664). The 3-phosphorylated phospholipids (PIP3s)generated by PI3-kinases act as second messengers recruiting kinaseswith lipid binding domains (including plekstrin homology (PH) regions),such as Akt and phosphoinositide-dependent kinase-1 (PDK1). Binding ofAkt to membrane PIP3s causes the translocation of Akt to the plasmamembrane, bringing Akt into contact with PDK1, which is responsible foractivating Akt. The tumor-suppressor phosphatase, PTEN, dephosphorylatesPIP3 and therefore acts as a negative regulator of Akt activation. ThePI3-kinases Akt and PDK1 are important in the regulation of manycellular processes including cell cycle regulation, proliferation,survival, apoptosis and motility and are significant components of themolecular mechanisms of diseases such as cancer, diabetes and immuneinflammation (Vivanco et al (2002) Nature Rev. Cancer 2:489; Phillips etal (1998) Cancer 83:41).

The PI3 kinase family comprises at least 15 different enzymessub-classified by structural homology and are divided into 3 classesbased on sequence homology and the product formed by enzyme catalysis.The class I PI3 kinases are composed of 2 subunits: a 110 kd catalyticsubunit and an 85 kd regulatory subunit. The regulatory subunits containSH2 domains and bind to tyrosine residues phosphorylated by growthfactor receptors with a tyrosine kinase activity or oncogene products,thereby inducing the PI3K activity of the p110 catalytic subunit whichphosphorylates its lipid substrate. Class I PI3 kinases are involved inimportant signal transduction events downstream of cytokines, integrins,growth factors and immunoreceptors, which suggests that control of thispathway may lead to important therapeutic effects such as modulatingcell proliferation and carcinogenesis. Class I PI3Ks can phosphorylatephosphatidylinositol (PI), phosphatidylinositol-4-phosphate, andphosphatidylinositol-4,5-biphosphate (PIP2) to producephosphatidylinositol-3-phosphate (PIP),phosphatidylinositol-3,4-biphosphate, andphosphatidylinositol-3,4,5-triphosphate, respectively. Class II PI3Ksphosphorylate PI and phosphatidylinositol-4-phosphate. Class III PI3Kscan only phosphorylate PI.

The main PI3-kinase isoform in cancer is the Class I PI3-kinase, p110α.(U.S. Pat. Nos. 5,824,492; 5,846,824; 6,274,327). Other isoforms areimplicated in cardiovascular and immune-inflammatory disease (Workman P(2004) “Inhibiting the phosphoinositide 3-kinase pathway for cancertreatment” Biochem Soc Trans 32:393-396; Patel et al (2004)“Identification of potent selective inhibitors of PI3K as candidateanticancer drugs” Proceedings of the American Association of CancerResearch (Abstract LB-247) 95th Annual Meeting, March 27-31, Orlando,Fla., USA; Ahmadi K and Waterfield M D (2004) “Phosphoinositide3-Kinase: Function and Mechanisms” Encyclopedia of Biological Chemistry(Lennarz W J, Lane M D eds) Elsevier/Academic Press).

Several components of the PI3-kinase/Akt/PTEN pathway are implicated inoncogenesis. In addition to growth factor receptor tyrosine kinases,integrin-dependent cell adhesion and G-protein coupled receptorsactivate PI3-kinase both directly and indirectly through adaptormolecules. Functional loss of PTEN (the most commonly mutatedtumor-suppressor gene in cancer after p53), oncogene mutations in PI3kinase (Samuels et al (2004) Science 304:554), amplification ofPI3-kinase and overexpression of Akt have been established in manymalignancies. In addition, persistent signaling through thePI3-kinase/Akt pathway by stimulation of the insulin-like growth factorreceptor is a mechanism of resistance to epidermal growth factorreceptor inhibitors such as AG1478 and trastuzumab. Oncogenic mutationsof p110alpha have been found at a significant frequency in colon,breast, brain, liver, ovarian, gastric, lung, and head and neck solidtumors. PTEN abnormalities are found in glioblastoma, melanoma,prostate, endometrial, ovarian, breast, lung, head and neck,hepatocellular, and thyroid cancers.

The levels of phosphatidylinositol-3,4,5-triphosphate (PIP3), theprimary product of PI3-kinase activation, increase upon treatment ofcells with a variety of agonists. PI3-kinase activation, therefore, isbelieved to be involved in a range of cellular responses including cellgrowth, differentiation, and apoptosis (Parker et al (1995) CurrentBiology, 5:577-99; Yao et al (1995) Science, 267:2003-05). Though thedownstream targets of phosphorylated lipids generated following PI3kinase activation have not been well characterized, emerging evidencesuggests that pleckstrin-homology domain- and FYVE-fingerdomain-containing proteins are activated when binding to variousphosphatidylinositol lipids (Sternmark et al (1999) J Cell Sci,112:4175-83; Lemmon et al (1997) Trends Cell Biol, 7:237-42). In vitro,some isoforms of protein kinase C (PKC) are directly activated by PIP3,and the PKC-related protein kinase, PKB, has been shown to be activatedby PI3 kinase (Burgering et al (1995) Nature, 376:599-602).

The initial purification and molecular cloning of PI3 kinase revealedthat it was a heterodimer consisting of p85 and p110 subunits (Otsu etal (1991) Cell 65:91-104; Hiles et al (1992) Cell 70:419-29). Sincethen, four distinct Class I PI3Ks have been identified, designated PI3Kα (alpha), β (beta), δ (delta), and ω (gamma), each consisting of adistinct 110 kDa catalytic subunit and a regulatory subunit. Morespecifically, three of the catalytic subunits, i.e., p110.alpha.,p110.beta. and p110.delta., each interact with the same regulatorysubunit, p85; whereas p110.gamma. interacts with a distinct regulatorysubunit, p101. As described below, the patterns of expression of each ofthese PI3Ks in human cells and tissues are also distinct.

The cellular functions of the individual isoforms of PI3 kinases are notcompletely elucidated. Bovine p110 alpha was described after cloning asrelated to the Saccharomyces cerevisiae protein: Vps34p, a proteininvolved in vacuolar protein processing. The recombinant p110 alphaproduct was also shown to associate with p85 alpha, to yield a PI3Kactivity in transfected COS-1 cells (Hiles et al. (1992), Cell,70:419-29). A second human p110 isoform was cloned and designated p110beta (Hu et al (1993) Mol Cell Biol 13:7677-88). This isoform is said toassociate with p85 in cells, and to be ubiquitously expressed, as p110beta mRNA has been found in numerous human and mouse tissues as well asin human umbilical vein endothelial cells, Jurkat human leukemic Tcells, 293 human embryonic kidney cells, mouse 3T3 fibroblasts, HeLacells, and NBT2 rat bladder carcinoma cells. Identification of the p110delta isoform of PI3 kinase is described in Chantry et al., J Biol Chem,272:19236-41 (1997). It was observed that the human p110 delta isoformis expressed in a tissue-restricted fashion. It is expressed at highlevels in lymphocytes and lymphoid tissues, suggesting that the proteinmight play a role in PI3 kinase-mediated signaling in the immune system(U.S. Pat. Nos. 5,858,753; 5,822,910; 5,985,589; WO 97/46688; andVanhaesebroeck et al (1997) Proc Natl Acad Sci USA, 94:4330-5).

In each of the PI3K alpha, beta, and delta subtypes, the p85 subunitacts to localize PI3 kinase to the plasma membrane by the interaction ofits SH2 domain with phosphorylated tyrosine residues (present in anappropriate sequence context) in target proteins (Rameh et al (1995)Cell, 83:821-30). Two isoforms of p85 have been identified, p85alpha,which is ubiquitously expressed, and p85 beta, which is primarily foundin the brain and lymphoid tissues (Volinia et al (1992) Oncogene,7:789-93). Association of the p85 subunit to the PI3 kinase p110 alpha,beta, or delta catalytic subunits appears to be required for thecatalytic activity and stability of these enzymes. In addition, thebinding of Ras proteins also upregulates PI3 kinase activity. Cloning ofp110 gamma revealed further complexity within the PI3K family of enzymes(Stoyanov et al (1995) Science, 269:690-93). The p110 gamma isoform isclosely related to p110 alpha and p110 beta (45-48% identity in thecatalytic domain), but does not make use of p85 as a targeting subunit.Instead, PI3K contains an additional domain termed a “pleckstrinhomology domain” near its amino terminus. This domain allows interactionof p110 gamma with the beta, gamma subunits of heterotrimeric G proteinsand this interaction appears to regulate its activity. The p101regulatory subunit for PI3Kgamma was originally cloned in swine, and thehuman ortholog identified subsequently (Krugmann et al (1999) J BiolChem, 274:17152-8).

Thus, PI3 kinases can be defined by their amino acid identity or bytheir activity. Additional members of this growing gene family includemore distantly related lipid and protein kinases including Vps34 TOR1,and TOR2 of Saccharomyces cerevisiae (and their mammalian homologs suchas FRAP and mTOR), the ataxia telangiectasia gene product (ATR) and thecatalytic subunit of DNA-dependent protein kinase (DNA-PK). Seegenerally, Hunter (1995) Cell, 83:1-4.

PI3 kinase also appears involved in leukocyte activation. Ap85-associated PI3 kinase activity has been shown to physicallyassociate with the cytoplasmic domain of CD28, which is an importantcostimulatory molecule for the activation of T-cells in response toantigen (Pages et al (1994) Nature, 369:327-29; Rudd, (1996) Immunity4:527-34). Activation of T cells through CD28 lowers the threshold foractivation by antigen and increases the magnitude and duration of theproliferative response. These effects are linked to increases in thetranscription of a number of genes including interleukin-2 (IL2), animportant T cell growth factor (Fraser et al (1991) Science,251:313-16). Mutation of CD28 such that it can no longer interact withPI3 kinase leads to a failure to initiate IL2 production, suggesting acritical role for PI3 kinase in T cell activation.

Inhibition of class I PI3 kinase induces apoptosis, blocks tumor inducedangiogenesis in vivo, and increases the radiosensitivity of certaintumors. At least two compounds, LY294002 and wortmannin, have beenwidely used as PI3 kinase inhibitors. These compounds, however, arenonspecific PI3K inhibitors, as they do not distinguish among the fourmembers of Class I PI3 kinases. For example, the IC50 values ofwortmannin (U.S. Pat. No. 6,703,414) against each of the various Class IPI3 kinases are in the range of 1-10 nanomolar (nM). LY294002(2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) is a well knownspecific inhibitor of class I PI3 kinases and has anti-cancer properties(Chiosis et al (2001) Bioorganic & Med. Chem. Lett. 11:909-913; Vlahoset al (1994) J. Biol. Chem. 269(7):5241-5248; Walker et al (2000) Mol.Cell 6:909-919; Fruman et al (1998) Ann Rev Biochem, 67:481-507).However, the anti-cancer applications of LY294002 are severely limitedby its lack of aqueous solubility and its poor pharmacokinetics.Moreover, LY294002 has no tissue specific properties and has beendemonstrated to be rapidly metabolized in animals. Because of thesefactors, LY294002 would need to be administered at frequent intervalsand thus has the potential to also inhibit PI3 kinases in normal cellsthereby leading to undesirable side effects.

There continues to be a need for class I PI3 kinase inhibitors withimproved pharmacokinetic and pharmacodynamic properties. The PI3kinase/Akt/PTEN pathway is thus an attractive target for cancer drugdevelopment since such agents would be expected to inhibitproliferation, reverse the repression of apoptosis and surmountresistance to cytotoxic agents in cancer cells. PI3 kinase inhibitorshave been reported (Yaguchi et al (2006) Jour. of the Nat. Cancer Inst.98(8):545-556; U.S. Pat. Nos. 6,608,056;. 6,608,053; 6,838,457;6,770,641; 6,653,320; 6,403,588; WO 2004017950; US 2004092561; WO2004007491; WO 2004006916; WO 2003037886; US 2003149074; WO 2003035618;WO 2003034997; US 2003158212; EP 1417976; US 2004053946; JP 2001247477;JP 08175990; JP 08176070). Wortmannin analogs have PI3 kinase activityin mammals (U.S. Pat. No. 6,703,414; WO 97/15658).

SUMMARY OF THE INVENTION

The invention relates generally to fused bicyclic thienopyrimidine andfuranopyrimidine compounds with anti-cancer activity, and morespecifically with PI3 kinase inhibitory activity. Certainhyperproliferative disorders are characterized by the modulation of PI3kinase function, for example by mutations or overexpression of theproteins. Accordingly, the compounds of the invention may be useful inthe treatment of hyperproliferative disorders such as cancer. Thecompounds may inhibit tumor growth in mammals and may be useful fortreating human cancer patients.

The invention also relates to methods of using the compounds for invitro, in situ, and in vivo diagnosis or treatment of mammalian cells,organisms, or associated pathological conditions.

More specifically, one aspect of the invention provides 4-morpholinothienopyrimidine and furanopyrimidine compounds of Formulas Ia and Ib:

and stereoisomers, geometric isomers, tautomers, solvates, metabolites,and pharmaceutically acceptable salts thereof, wherein X is O or S.Groups R¹, R² and R³ are as defined herein.

Another aspect of the invention provides a pharmaceutical compositioncomprising a thienopyrimidine or furanopyrimidine compound of FormulasIa or Ib and a pharmaceutically acceptable carrier. The pharmaceuticalcomposition may further comprise one or more additional therapeuticagents selected from anti-proliferative agents, anti-inflammatoryagents, immunomodulatory agents, neurotropic factors, agents fortreating cardiovascular disease, agents for treating liver disease,anti-viral agents, agents for treating blood disorders, agents fortreating diabetes, and agents for treating immunodeficiency disorders.

Another aspect of the invention provides methods of inhibiting PI3kinase activity, comprising contacting a PI3 kinase with an effectiveinhibitory amount of a compound of Formula Ia or Ib, or a stereoisomer,geometric isomer, tautomer, solvate, metabolite, or pharmaceuticallyacceptable salt or prodrug thereof.

Another aspect of the invention provides methods of preventing ortreating a disease or disorder modulated by PI3 kinases, comprisingadministering to a mammal in need of such treatment an effective amountof a compound of Formula Ia or Ib, or a stereoisomer, geometric isomer,tautomer, solvate, metabolite, or pharmaceutically acceptable salt orprodrug thereof. Examples of such diseases, conditions and disordersinclude, but are not limited to, hyperproliferative disorders (e.g.,cancer, including melanoma and other cancers of the skin),neurodegeneration, cardiac hypertrophy, pain, migraine, neurotraumaticdiseases, stroke, diabetes, hepatomegaly, cardiovascular disease,Alzheimer's disease, cystic fibrosis, viral diseases, autoimmunediseases, atherosclerosis, restenosis, psoriasis, allergic disorders,inflammation, neurological disorders, hormone-related diseases,conditions associated with organ transplantation, immunodeficiencydisorders, destructive bone disorders, proliferative disorders,infectious diseases, conditions associated with cell death,thrombin-induced platelet aggregation, chronic myelogenous leukemia(CML), liver disease, pathologic immune conditions involving T cellactivation, and CNS disorders.

Another aspect of the invention provides methods of preventing ortreating a hyperproliferative disorder, comprising administering to amammal in need of such treatment an effective amount of a compound ofFormula Ia or Ib, or a stereoisomer, geometric isomer, tautomer,solvate, metabolite, or pharmaceutically acceptable salt or prodrugthereof, alone or in combination with one or more additional compoundshaving anti-hyperproliferative properties.

In a further aspect the present invention provides a method of using acompound of this invention to treat a disease or condition modulated byPI3 kinase in a mammal.

An additional aspect of the invention is the use of a compound of thisinvention in the preparation of a medicament for the treatment orprevention of a disease or condition modulated by PI3 kinase in amammal.

Another aspect of the invention includes kits comprising a compound ofFormula Ia or Ib, or a stereoisomer, geometric isomer, tautomer,solvate, metabolite, or pharmaceutically acceptable salt or prodrugthereof, a container, and optionally a package insert or labelindicating a treatment.

Another aspect of the invention includes methods of preparing, methodsof separating, and methods of purifying compounds of Formula Ia and Ib.

Additional advantages and novel features of this invention shall be setforth in part in the description that follows, and in part will becomeapparent to those skilled in the art upon examination of the followingspecification or may be learned by the practice of the invention. Theadvantages of the invention may be realized and attained by means of theinstrumentalities, combinations, compositions, and methods particularlypointed out in the appended claims.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature, patents, and similar materials differs from or contradictsthis application, including but not limited to defined terms, termusage, described techniques, or the like, this application controls.

Definitions

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms, wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described below. Examples ofalkyl groups include, but are not limited to, methyl (Me, —CH₃), ethyl(Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr,i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (1-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, and the like.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to twelve carbon atoms with at least one siteof unsaturation, i.e., a carbon-carbon, sp² double bond, wherein thealkenyl radical may be optionally substituted independently with one ormore substituents described herein, and includes radicals having “cis”and “trans” orientations, or alternatively, “E” and “Z” orientations.Examples include, but are not limited to, ethylenyl or vinyl (—CH═CH₂),allyl (—CH₂CH═CH₂), and the like.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of two to twelve carbon atoms with at least one site ofunsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynylradical may be optionally substituted independently with one or moresubstituents described herein. Examples include, but are not limited to,ethynyl (—C≡CH), propynyl (propargyl, —CH₂C≡CH), and the like.

The terms “carbocycle”, “carbocyclyl”, “carbocyclic ring” and“cycloalkyl” refer to a monovalent non-aromatic, saturated or partiallyunsaturated ring having 3 to 12 carbon atoms as a monocyclic ring or 7to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycles having 7 to12 atoms can be arranged, for example, as a bicyclo[4,5], [5,5], [5,6]or [6,6] system, and bicyclic carbocycles having 9 or 10 ring atoms canbe arranged as a bicyclo[5,6] or [6,6] system, or as bridged systemssuch as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane andbicyclo[3.2.2]nonane. Examples of monocyclic carbocycles include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl, cyclododecyl, and the like.

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbonatoms derived by the removal of one hydrogen atom from a single carbonatom of a parent aromatic ring system. Some aryl groups are representedin the exemplary structures as “Ar”. Aryl includes bicyclic radicalscomprising an aromatic ring fused to a saturated, partially unsaturatedring, or aromatic carbocyclic or heterocyclic ring. Typical aryl groupsinclude, but are not limited to, radicals derived from benzene (phenyl),substituted benzenes, naphthalene, anthracene, biphenyl, indenyl,indanyl, 1,2-dihydronapthalene, 1,2,3,4-tetrahydronapthyl, and the like.Aryl groups are optionally substituted independently with one or moresubstituents described herein.

The terms “heterocycle,” “heterocyclyl” and “heterocyclic ring” are usedinterchangeably herein and refer to a saturated or a partiallyunsaturated (i.e., having one or more double and/or triple bonds withinthe ring) carbocyclic radical of 3 to 20 ring atoms in which at leastone ring atom is a heteroatom selected from nitrogen, oxygen and sulfur,the remaining ring atoms being C, where one or more ring atoms isoptionally substituted independently with one or more substituentsdescribed below. A heterocycle may be a monocycle having 3 to 7 ringmembers (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O,P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atomsand 1 to 6 heteroatoms selected from N, O, P, and S), for example: abicyclo[4,5], [5,5], [5,6], or [6,6] system. Heterocycles are describedin Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and9; “The Chemistry of Heterocyclic Compounds, A series of Monographs”(John Wiley & Sons, New York, 1950 to present), in particular Volumes13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. Theheterocyclyl may be a carbon radical or heteroatom radical. The term“heterocycle” includes heterocycloalkoxy. “Heterocyclyl” also includesradicals where heterocycle radicals are fused with a saturated,partially unsaturated ring, or aromatic carbocyclic or heterocyclicring. Examples of heterocyclic rings include, but are not limited to,pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl,3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 3H-indolyl quinolizinyl and N-pyridyl ureas.Spiro moieties are also included within the scope of this definition.Examples of a heterocyclic group wherein 2 ring carbon atoms aresubstituted with oxo (═O) moieties are pyrimidinonyl and1,1-dioxo-thiomorpholinyl. The heterocycle groups herein are optionallysubstituted independently with one or more substituents describedherein.

The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-,or 7-membered rings, and includes fused ring systems (at least one ofwhich is aromatic) of 5-20 atoms, containing one or more heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Examples ofheteroaryl groups are pyridinyl (including, for example,2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl(including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.Heteroaryl groups are optionally substituted independently with one ormore substituents described herein.

The heterocycle or heteroaryl groups may be carbon (carbon-linked),nitrogen (nitrogen-linked) or oxygen (oxygen-linked) attached where suchis possible. By way of example and not limitation, carbon bondedheterocycles or heteroaryls are bonded at position 2, 3, 4, 5, or 6 of apyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4,or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole ortetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole orthiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole,position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine,position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5,6, 7, or 8 of an isoquinoline.

By way of example and not limitation, nitrogen bonded heterocycles orheteroaryls are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or β-carboline.

“Fused bicyclic C₄-C₂₀ heterocyclyl” and “Fused bicyclic C₁-C₂₀heteroaryl” containing one or more heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, differ only by their aromaticcharacter, and have two rings fused together, i.e. share a common bond.Fused bicyclic heterocyclyl and heteroaryl radicals may be attached tothe C-2 position of the pyrimidine ring according to Formulas Ia and Ibat any carbon (carbon-linked), or nitrogen (nitrogen-linked) atom of thefused bicyclic C₄-C₂₀ heterocyclyl or fused bicyclic C₁-C₂₀ heteroarylgroup R³ group. Fused bicyclic heterocyclyl and heteroaryl radicalsinclude, but are not limited to: 1H-indazole, 1H-indole, indolin-2-one,1-(indolin-1-yl)ethanone, 1H-benzo[d][1,2,3]triazole,1H-pyrazolo[3,4-b]pyridine, 1H-pyrazolo[3,4-d]pyrimidine,1H-benzo[d]imidazole, 1H-benzo[d]imidazol-2(3H)-one,1H-pyrazolo[3,4-c]pyridine, 1H-pyrrolo[2,3-c]pyridine,3H-imidazo[4,5-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, 7H-purine,1H-pyrazolo[4,3-d]pyrimidine, 5H-pyrrolo[3,2-d]pyrimidine,2-amino-1H-purin-6(9H)-one, quinoline, quinazoline, quinoxaline,isoquinoline, isoquinolin-1(2H)-one, 3,4-dihydroisoquinolin-1(2H)-one,3,4-dihydroquinolin-2(1H)-one, quinazolin-2(1H)-one,quinoxalin-2(1H)-one, 1,8-naphthyridine, pyrido[3,4-d]pyrimidine, andpyrido[3,2-b]pyrazine. Fused bicyclic heterocycles and fused bicyclicheteroaryls are optionally substituted independently with one or moresubstituents described herein.

The substituent groups that alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with includeF, Cl, Br, I, CN, CF₃, —NO₂, oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰,—C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹,—NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹¹, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹²,OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰, —OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰),—OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹), SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰), —SC(═Y)R¹⁰, —SC(═Y)OR¹⁰,—SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substituted alkyl, C₂-C₈ optionallysubstituted alkenyl, C₂-C₈ optionally substituted alkynyl, C₃-C₁₂optionally substituted carbocyclyl, C₂-C₂₀ optionally substitutedheterocyclyl, C₆-C₂₀ optionally substituted aryl, C₁-C₂₀ optionallysubstituted heteroaryl, —(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and(CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹

The terms “treat” and “treatment” refer to both therapeutic treatmentand prophylactic or preventative measures, wherein the object is toprevent or slow down (lessen) an undesired physiological change ordisorder, such as the development or spread of cancer. For purposes ofthis invention, beneficial or desired clinical results include, but arenot limited to, alleviation of symptoms, diminishment of extent ofdisease, stabilized (i.e., not worsening) state of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.Those in need of treatment include those already with the condition ordisorder as well as those prone to have the condition or disorder orthose in which the condition or disorder is to be prevented.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein. In the case of cancer, the therapeuticallyeffective amount of the drug may reduce the number of cancer cells;reduce the tumor size; inhibit (i.e., slow to some extent and preferablystop) cancer cell infiltration into peripheral organs; inhibit (i.e.,slow to some extent and preferably stop) tumor metastasis; inhibit, tosome extent, tumor growth; and/or relieve to some extent one or more ofthe symptoms associated with the cancer. To the extent the drug mayprevent growth and/or kill existing cancer cells, it may be cytostaticand/or cytotoxic. For cancer therapy, efficacy can be measured, forexample, by assessing the time to disease progression (TTP) and/ordetermining the response rate (RR).

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth. A “tumor” comprises one or more cancerouscells. Examples of cancer include, but are not limited to, carcinoma,lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. Moreparticular examples of such cancers include squamous cell cancer (e.g.,epithelial squamous cell cancer), lung cancer including small-cell lungcancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lungand squamous carcinoma of the lung, cancer of the peritoneum,hepatocellular cancer, gastric or stomach cancer includinggastrointestinal cancer, pancreatic cancer, glioblastoma, cervicalcancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breastcancer, colon cancer, rectal cancer, colorectal cancer, endometrial oruterine carcinoma, salivary gland carcinoma, kidney or renal cancer,prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, analcarcinoma, penile carcinoma, as well as head and neck cancer.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer. Examples of chemotherapeutic agents includeErlotinib (TARCEVA®, Genentech/OSI Pharm.), Bortezomib (VELCADE®,Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent(SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate(GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis), Oxaliplatin(Eloxatin®, Sanofi), 5-FU (5-fluorouracil), Leucovorin, Rapamycin(Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKBRB®, GSK572016, GlaxoSmith Kline), Lonafamib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs),and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen),alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines suchas benzodopa, carboquone, meturedopa, and uredopa; ethylenimines andmethylamelamines including altretamine, triethylenemelamine,triethylenephosphoramide, triethylenethiophosphoramide andtrimethylomelamine; acetogenins (especially bullatacin andbullatacinone); a camptothecin (including the synthetic analogtopotecan); bryostatin; callystatin; CC-1065 (including its adozelesin,carzelesin and bizelesin synthetic analogs); cryptophycins (particularlycryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (includingthe synthetic analogs, KW-2189 and CB1-TM1); eleutherobin;pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such aschlorambucil, chlomaphazine, chlorophosphamide, estramustine,ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride,melphalan, novembichin, phenesterine, prednimustine, trofosfamide,uracil mustard; nitrosureas such as carmustine, chlorozotocin,fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such asthe enediyne antibiotics (e.g., calicheamicin, especially calicheamicingamma1I and calicheamicin omegaI1 (Angew Chem. Intl. Ed. Engl. (1994)33:183-186); dynemicin, including dynemicin A; bisphosphonates, such asclodronate; an esperamicin; as well as neocarzinostatin chromophore andrelated chromoprotein enediyne antibiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®(doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL®(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® (doxetaxel; Rhône-Poulenc Rorer, Antony, France);chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine;methotrexate; platinum analogs such as cisplatin and carboplatin;vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine;NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate;daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11;topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO);retinoids such as retinoic acid; and pharmaceutically acceptable salts,acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” are: (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including NOLVADEX®;tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifinecitrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase,which regulates estrogen production in the adrenal glands, such as, forexample, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrolacetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole,RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX®(anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide,nilutamide, bicalutamide, leuprolide, and goserelin; as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors; (v) lipid kinase inhibitors; (vi) antisenseoligonucleotides, particularly those which inhibit expression of genesin signaling pathways implicated in aberrant cell proliferation, suchas, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGFexpression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors;(viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®,LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; a topoisomerase 1 inhibitorsuch as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such asbevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptablesalts, acids and derivatives of any of the above.

The term “prodrug” as used in this application refers to a precursor orderivative form of a compound of the invention that is less cytotoxic tocells compared to the parent compound or drug and is capable of beingenzymatically or hydrolytically activated or converted into the moreactive parent form. See, e.g., Wilman, “Prodrugs in Cancer Chemotherapy”Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast(1986) and Stella et al., “Prodrugs: A Chemical Approach to TargetedDrug Delivery,” Directed Drug Delivery, Borchardt et al., (ed.), pp.247-267, Humana Press (1985). The prodrugs of this invention include,but are not limited to, phosphate-containing prodrugs,thiophosphate-containing prodrugs, sulfate-containing prodrugs,peptide-containing prodrugs, D-amino acid-modified prodrugs,glycosylated prodrugs, β-lactam-containing prodrugs, optionallysubstituted phenoxyacetamide-containing prodrugs, optionally substitutedphenylacetamide-containing prodrugs, 5-fluorocytosine and other5-fluorouridine prodrugs which can be converted into the more activecytotoxic free drug. Examples of cytotoxic drugs that can be derivatizedinto a prodrug form for use in this invention include, but are notlimited to, compounds of the invention and chemotherapeutic agents suchas described above.

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. Metabolites of a compound may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchproducts may result for example from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzymatic cleavage, and the like, of the administered compound.Accordingly, the invention includes metabolites of compounds of theinvention, including compounds produced by a process comprisingcontacting a compound of this invention with a mammal for a period oftime sufficient to yield a metabolic product thereof.

A “liposome” is a small vesicle composed of various types of lipids,phospholipids and/or surfactant which is useful for delivery of a drug(such as the PI3 kinase inhibitors disclosed herein and, optionally, achemotherapeutic agent) to a mammal. The components of the liposome arecommonly arranged in a bilayer formation, similar to the lipidarrangement of biological membranes.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand l or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

The phrase “pharmaceutically acceptable salt” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe invention. Exemplary salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. A pharmaceuticallyacceptable salt may involve the inclusion of another molecule such as anacetate ion, a succinate ion or other counter ion. The counter ion maybe any organic or inorganic moiety that stabilizes the charge on theparent compound. Furthermore, a pharmaceutically acceptable salt mayhave more than one charged atom in its structure. Instances wheremultiple charged atoms are part of the pharmaceutically acceptable saltcan have multiple counter ions. Hence, a pharmaceutically acceptablesalt can have one or more charged atoms and/or one or more counter ion.

If the compound of the invention is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,methanesulfonic acid, phosphoric acid and the like, or with an organicacid, such as acetic acid, maleic acid, succinic acid, mandelic acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, a pyranosidyl acid, such as glucuronic acid orgalacturonic acid, an alpha hydroxy acid, such as citric acid ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the compound of the invention is an acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide or alkaline earth metal hydroxide, or the like. Illustrativeexamples of suitable salts include, but are not limited to, organicsalts derived from amino acids, such as glycine and arginine, ammonia,primary, secondary, and tertiary amines, and cyclic amines, such aspiperidine, morpholine and piperazine, and inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum and lithium.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.The term “hydrate” refers to the complex where the solvent molecule iswater.

The term “protecting group” refers to a substituent that is commonlyemployed to block or protect a particular functionality while reactingother functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protectinggroup” refers to a substituent of a hydroxy group that blocks orprotects the hydroxy functionality. Suitable protecting groups includeacetyl and silyl. A “carboxy-protecting group” refers to a substituentof the carboxy group that blocks or protects the carboxy functionality.Common carboxy-protecting groups include phenylsulfonylethyl,cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a generaldescription of protecting groups and their use, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991.

The terms “compound of this invention,” and “compounds of the presentinvention” and “compounds of Formula Ia and Ib” include compounds ofFormulas Ia and Ib and stereoisomers, geometric isomers, tautomers,solvates, metabolites, and pharmaceutically acceptable salts andprodrugs thereof.

The term “mammal” includes, but is not limited to, humans, mice, rats,guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep, andpoultry.

PI3 Kinase Inhibitor Compounds

The present invention provides 4-morpholino thienopyrimidine andfuranopyrimidine compounds, and pharmaceutical formulations thereof,that are potentially useful in the treatment of diseases, conditionsand/or disorders modulated by PI3 kinases. The compounds may inhibitp110 isoforms including alpha, beta, gamma, and delta as pan inhibitors.The compounds may be p110 isoform selective inhibitors by selectiveinhibition of one of the p110 isoforms.

More specifically, the present invention provides compounds of FormulasIa and Ib.

and stereoisomers, geometric isomers, tautomers, solvates, metabolites,and pharmaceutically acceptable salts thereof, wherein:

X is O or S;

R¹ is selected from H, F, Cl, Br, I, CN, —CR¹⁴R¹⁵—NR¹⁶R¹⁷,—CR¹⁴R¹⁵—NHR¹⁰, —(CR¹⁴R¹⁵)_(t)NR¹⁰R¹¹, —C(R¹⁴R¹⁵)_(n)NR¹²C(═Y)R¹⁰,—(CR¹⁴R¹⁵)_(n)NR¹²S(O)₂R¹⁰, —(CR¹⁴R¹⁵)_(m)OR¹⁰, —(CR¹⁴R¹⁵)_(n)S(O)₂R¹⁰,—(CR¹⁴R¹⁵)_(n)S(O)₂NR¹⁰R¹¹, —C(OR¹⁰)R¹¹R¹⁴, —C(R¹⁴)═CR¹⁸R¹⁹, —C(═Y)R¹⁰,—C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —C(═Y)NR¹²OR¹⁰, —C(═O)NR¹²S(O)₂R¹⁰,—C(═O)NR¹² (CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —NO₂, —NHR¹², —NR¹²C(═Y)R¹¹,—NR¹²C(═Y)OR¹¹, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²S(O)₂R¹⁰, —NR¹²SO₂NR¹⁰R¹¹,—S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, C₂-C₁₂ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀aryl, or C₁-C₂₀ heteroaryl;

R² is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂, —C(═Y)R¹⁰,—C(—Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl;

R³ is fused bicyclic C₄-C₂₀ heterocyclyl or fused bicyclic C₁-C₂₀heteroaryl;

R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀heteroaryl,

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedoptionally form a saturated, partially unsaturated or fully unsaturatedC₃-C₂₀ heterocyclic ring optionally containing one or more additionalring atoms selected from N, O or S, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom oxo, (CH₂)_(m)OR¹⁰NR¹⁰R¹¹, CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰,NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹, C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl andC₁-C₂₀ heteroaryl;

R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂ alkyl, or—(CH₂)_(n)-aryl,

or R¹⁴ and R¹⁵ together with the atoms to which they are attached form asaturated or partially unsaturated C₃-C₁₂ carbocyclic ring,

R¹⁶ and R¹⁷ are independently H, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₁₂ carbocyclyl, or C₆-C₂₀ aryl,

R¹⁸ and R¹⁹ together with the carbon to which they are attached form aC₃-C₂₀ heterocyclic ring,

where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl andheteroaryl are optionally substituted with one or more groupsindependently selected from F, Cl, Br, I, CN, CF₃, —NO₂, oxo, R¹⁰,—C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R^(11;)

Y is O, S, or NR¹²;

m is 0, 1, 2, 3, 4, 5 or 6;

n is 1, 2, 3, 4, 5 or 6; and

t is 2, 3, 4, 5 or 6.

In another embodiment, the present invention provides compounds ofFormulas Ia and Ib wherein:

X is O or S;

R¹ is selected from H, —CR¹⁴R¹⁵—NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(t)NR¹⁰R¹¹,—C(R¹⁴R¹⁵)_(n)NR¹²C(═Y)R¹⁰, —(CR¹⁴R¹⁵)_(n)NR¹²S(O)₂R¹⁰,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —(CR¹⁴R¹⁵)_(n)S(O)₂R¹⁰, —(CR¹⁴R¹⁵)_(n)S(O)₂NR¹⁰R¹¹,—C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —C(═Y)NR¹²OR¹⁰,—C(═O)NR¹²S(O)₂R¹⁰, —C(═O)NR¹²(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —NO₂, —NHR¹²,—NR¹²C(═Y)R¹¹, —NR¹²C(═Y)OR¹¹, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²S(O)₂R¹⁰,—NR¹²SO₂NR¹⁰R¹¹, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —SC(═Y)R¹⁰, —SC(═Y)OR¹⁰,C₂-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl;

R² is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂, —C(═Y)R¹⁰,—C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₂-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl;

R³ is fused bicyclic C₂-C₂₀ heterocyclyl or fused bicyclic C₁-C₂₀heteroaryl;

R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀heteroaryl,

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedoptionally form a saturated, partially unsaturated or fully unsaturatedC₃-C₂₀ heterocyclic ring optionally containing one or more additionalring atoms selected from N, O or S, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom oxo, (CH₂)_(n)OR¹⁰, NR¹⁰R¹¹, CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰,NR¹²C(═Y)R¹¹, C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl and C₁-C₂₀heteroaryl;

R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂ alkyl, or—(CH₂)_(n)-aryl,

or R¹⁴ and R¹⁵ together with the atoms to which they are attached form asaturated or partially unsaturated C₃-C₁₂ carbocyclic ring,

where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl andheteroaryl are optionally substituted with one or more groupsindependently selected from F, Cl, Br, I, CN, CF₃, —NO₂, oxo, —C(═Y)R¹⁰,—C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹¹, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰,═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰, —OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰),—OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹), SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰), —SC(═Y)R¹⁰, —SC(═Y)OR¹⁰,—SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, C₁-C₂₀ heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R^(11;)

Y is O, S, or NR¹²;

m is 0, 1, 2, 3, 4, 5 or 6;

n is 1, 2, 3, 4, 5 or 6; and

t is 2, 3, 4, 5 or 6.

Formula Ia and Ib compounds are regioisomers, i.e. differ by theplacement of atom X in the thienopyrimidine (X=sulfur) orfuranopyrimidine (X=oxygen) ring system. Parent molecules of Formula Iaand Ib compounds are:

Compounds of the invention thus include both regioisomers of each of the4-morpholino thienopyrimidine and 4-morpholino furanopyrimidinecompounds, and the substituted forms as described by R¹, R², and R³herein:

In certain embodiments, R¹ is —(CR¹⁴R¹⁵)_(t)NR¹⁰R¹¹ where t is 2 or 3,and R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform the C₃-C₂₀ heterocyclic ring.

In certain embodiments, R¹ is —(CR¹⁴R¹⁵)_(n)NR¹²S(O)₂R¹⁰ where n is 1 or2; R¹², R¹⁴, and R¹⁵ are independently selected from H and C₁-C₁₂ alkyl;and R¹⁰ is C₁-C₁₂ alkyl or C₆-C₂₀ aryl.

In certain embodiments, R¹ is —(CR¹⁴R¹⁵)_(n)OR¹⁰ where n is 1 or 2, andR¹⁰, R¹⁴, and R¹⁵ are independently selected from H and C₁-C₁₂ alkyl.

In certain embodiments, R¹ is —(CR¹⁴R¹⁵)_(n)S(O)₂R¹⁰ where n is 1 or 2,and R¹⁴ and R¹⁵ are H. R¹⁰ may be C₁-C₁₂ alkyl or C₆-C₂₀ aryl.

In certain embodiments, R¹ is —(CR¹⁴R¹⁵)_(n)S(O)₂NR¹⁰R¹¹ where n is 1 or2, and R¹⁴ and R¹⁵ are H.

In certain embodiments, R¹ is —C(═Y)NR¹⁰R¹¹ where Y is O, and R¹⁰ andR¹¹ together with the nitrogen to which they are attached form theC₂-C₂₀ heterocyclic ring. R¹⁰ and R¹¹ together with the nitrogen towhich they are attached may form a C₂-C₂₀ heterocyclic ring selectedfrom morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl.

In certain embodiments, R¹ is —C(═Y)NR¹⁰R¹¹ where Y is O, and R¹⁰ andR¹¹ are independently selected from H and C₁-C₁₂ alkyl.

In certain embodiments, R¹ is —C(═Y)NR¹⁰R¹¹ where Y is O, and R¹⁰ andR¹¹ are independently selected from H, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, and C₁-C₂₀ heteroaryl.

In certain embodiments, R¹ is —NHR¹² where R¹² is C₃-C₁₂ carbocyclyl,C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl. R¹² may bephenyl or 4-pyridyl.

In certain embodiments, R¹ is —NR¹²C(═Y)R¹¹ where Y is O, R¹² is H orC₁-C₁₂ alkyl, and R¹¹ is C₁-C₁₂ alkyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl. R¹¹ includes, but isnot limited to, methyl, ethyl, propyl, isopropyl, isobutyl,2,2-dimethylpropyl, and tert-butyl. R¹¹ also includes, but is notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In certain embodiments, R¹ is —NR¹²S(O)₂R¹⁰ where R¹² is H or C₁-C₁₂alkyl, and R¹⁰ is C₁-C₁₂ alkyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl,C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl.

In certain embodiments, R¹ is S(O)₂NR¹⁰R¹¹ where R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached form a C₂-C₂₀ heterocyclicring selected from morpholinyl, piperidinyl, piperazinyl, andpyrrolidinyl.

In certain embodiments, R¹ is S(O)₂NR¹⁰R¹¹ where R¹⁰ and R¹¹ areindependently selected from H and C₁-C₁₂ alkyl. R¹⁰ and R¹¹ may beindependently selected from H, substituted ethyl, and substitutedpropyl.

In certain embodiments, R¹ is C₂-C₁₂ alkyl.

In certain embodiments, R¹ is C₂-C₈ alkenyl.

In certain embodiments, R¹ is C₂-C₈ alkynyl. The C₂-C₈ alkynyl may besubstituted with C₂-C₂₀ heterocyclyl, which includes, but is not limitedto, morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl.

In certain embodiments, R¹ is selected from the groups:

In certain embodiments, R¹ is C₆-C₂₀ aryl, such as phenyl.

In certain embodiments, R¹ is C₃-C₁₂ carbocyclyl.

In certain embodiments, R¹ is C₂-C₂₀ heterocyclyl.

In certain embodiments, R¹ is C₁-C₂₀ heteroaryl, such as 2-pyridyl,3-pyridyl, 4-pyridyl, or 5-pyrimidinyl.

In certain embodiments, R² is H.

In certain embodiments, R² is methyl (CH₃).

Exemplary embodiments of R³ include, but are not limited to:1H-indazole, 1H-indole, indolin-2-one, 1-(indolin-1-yl)ethanone,1H-benzo[d][1,2,3]triazole, 1H-pyrazolo[3,4-b]pyridine,1H-pyrazolo[3,4-d]pyrimidine, 1H-benzo[d]imidazole,1H-benzo[d]imidazol-2(3H)-one, 1H-pyrazolo[3,4-c]pyridine,1H-pyrrolo[2,3-c]pyridine, 3H-imidazo[4,5-c]pyridine,7H-pyrrolo[2,3-d]pyrimidine, 7H-purine, 1H-pyrazolo[4,3-d]pyrimidine,5H-pyrrolo[3,2-d]pyrimidine, 2-amino-1H-purin-6(9H)-one, quinoline,quinazoline, quinoxaline, isoquinoline, isoquinolin-1(2H)-one,3,4-dihydroisoquinolin-1(2H)-one, 3,4-dihydroquinolin-2(1H)-one,quinazolin-2(1H)-one, quinoxalin-2(1H)-one, 1,8-naphthyridine,pyrido[3,4-d]pyrimidine, and pyrido[3,2-b]pyrazine.

The attachment site of the R³ group to the C-2 position of thepyrimidine ring according to Formulas Ia and Ib may be at any carbon(carbon-linked), nitrogen (nitrogen-linked) or oxygen (oxygen-linked)atom of the fused bicyclic C₄-C₂₀ heterocyclyl or fused bicyclic C₁-C₂₀heteroaryl group R³ group.

Exemplary embodiments of R³ include the following groups, where the wavyline indicates the site of attachment to the pyrimidine ring:

where the wavy line indicates the site of attachment.

Exemplary embodiments of R³ include fused bicyclic C₄-C₂₀ heterocyclyland fused bicyclic C₁-C₂₀ heteroaryl, including those exemplified above,substituted with one or more groups independently selected from F, Cl,Br, I, CN, CF₃, —NO₂, oxo, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰,—NR¹²C(═Y)OR¹¹, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰,—OC(═Y)OR¹⁰, —OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹),—OP(OR¹⁰)(OR¹¹), SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰),—S(O)₂(OR¹⁰), —SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl,C₆-C₂₀ aryl, C₁-C₂₀ heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R^(11.)

The Formula Ia and Ib compounds of the invention may contain asymmetricor chiral centers, and therefore exist in different stereoisomericforms. It is intended that all stereoisomeric forms of the compounds ofthe invention, including but not limited to, diastereomers, enantiomersand atropisomers, as well as mixtures thereof such as racemic mixtures,form part of the present invention.

In addition, the present invention embraces all geometric and positionalisomers. For example, if a Formula Ia and Ib compound incorporates adouble bond or a fused ring, the cis- and trans-forms, as well asmixtures thereof, are embraced within the scope of the invention. Boththe single positional isomers and mixture of positional isomers are alsowithin the scope of the present invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms.

The compounds of the present invention may also exist in differenttautomeric forms, and all such forms are embraced within the scope ofthe invention. The term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. All isotopes of any particular atom or elementas specified are contemplated within the scope of the compounds of theinvention, and their uses. Exemplary isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S,¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I. Certain isotopically-labeled compounds of thepresent invention (e.g., those labeled with ³H and ¹⁴C) are useful incompound and/or substrate tissue distribution assays. Tritiated (³H) andcarbon-14 (¹⁴C) isotopes are useful for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., 2H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C and ¹⁸Fare useful for positron emission tomography (PET) studies to examinesubstrate receptor occupancy. Isotopically labeled compounds of thepresent invention can generally be prepared by following proceduresanalogous to those disclosed in the Schemes and/or in the Examplesherein below, by substituting an isotopically labeled reagent for anon-isotopically labeled reagent.

Preparation of Formula Ia and Ib Compounds

Thienopyrimidine and furanopyrimidine compounds of Formula Ia and Ib maybe synthesized by synthetic routes that include processes analogous tothose well-known in the chemical arts, particularly in light of thedescription contained herein. The starting materials are generallyavailable from commercial sources such as Aldrich Chemicals (Milwaukee,Wis.) or are readily prepared using methods well known to those skilledin the art (e.g., prepared by methods generally described in Louis F.Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley,N.Y. (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4,Aufl. ed. Springer-Verlag, Berlin, including supplements (also availablevia the Beilstein online database).

In certain embodiments, compounds of Formula Ia or Ib may be readilyprepared using procedures well-known to prepare thiophenes, furans,pyrimidines (U.S. Pat. Nos. 6,608,053; 6,492,383; 6,232,320; 6,187,777;3,763,156 3,661,908; 3,475,429; 5,075,305; US 2003/220365; GB 1393161;WO 93/13664;); and other heterocycles, which are described in:Comprehensive Heterocyclic Chemistry, Editors Katritzky and Rees,Pergamon Press, 1984.

Compounds of Formula Ia and Ib may be prepared singly or as compoundlibraries comprising at least 2, for example 5 to 1,000 compounds, or 10to 100 compounds. Libraries of compounds of Formula Ia or Ib may beprepared by a combinatorial ‘split and mix’ approach or by multipleparallel syntheses using either solution phase or solid phase chemistry,by procedures known to those skilled in the art. Thus according to afurther aspect of the invention there is provided a compound librarycomprising at least 2 compounds, or pharmaceutically acceptable saltsthereof.

For illustrative purposes, Schemes 1-7 show general methods forpreparing the compounds of the present invention as well as keyintermediates. For a more detailed description of the individualreaction steps, see the Examples section below. Those skilled in the artwill appreciate that other synthetic routes may be used to synthesizethe inventive compounds. Although specific starting materials andreagents are depicted in the Schemes and discussed below, other startingmaterials and reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

In preparing compounds of Formulas Ia and Ib, protection of remotefunctionality (e.g., primary or secondary amine) of intermediates may benecessary. The need for such protection will vary depending on thenature of the remote functionality and the conditions of the preparationmethods. Suitable amino-protecting groups include acetyl,trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethylenoxycarbonyl (Fmoc). The need for such protection isreadily determined by one skilled in the art. For a general descriptionof protecting groups and their use, see T. W. Greene, Protective Groupsin Organic Synthesis, John Wiley & Sons, New York, 1991.

Scheme 1 shows a general method for preparation of the thienopyrimidineand furanopyrimidine intermediates 55 and 56 from 2-carboxyester,3-amino thiophene (X═S) and furan (X═O), and 2-amino, 3-carboxy esterthiophene (X═S) and furan (X═O) reagents, respectively 51 and 52,wherein X is O or S; Hal is Cl, Br, or I; and R¹, R², and R¹⁰ are asdefined for Formula Ia and Ib compounds, or precursors or prodrugsthereto.

Scheme 2 shows a general method for selectively displacing a 4-halidefrom bis-halo thienopyrimidine and 4-morpholino furanopyrimidineintermediates 57 and 58 with morpholine under basic conditions in anorganic solvent to prepare 2-halo, 4-morpholino thienopyrimidine and4-morpholino furanopyrimidine compounds 59 and 60 respectively, whereinX is O or S; Hal is Cl, Br, or I; and R¹ and R² are as defined forFormula Ia and Ib compounds, or precursors or prodrugs thereto.

Scheme 3 shows a general method for derivatizing the 6-position of2-halo, 4-morpholino, 6-hydrogen thienopyrimidine and 4-morpholinofuranopyrimidine compounds 61 and 62 where R¹¹ is H. Treating 61 or 62with a lithiating reagent to remove the 6 position proton, followed byadding an acylating reagent R¹⁰C(O)Z where Z is a leaving group, such ashalide, NHS ester, carboxylate, or dialkylamino, gives 2-halo,4-morpholino, 6-acyl thienopyrimidine and 4-morpholino furanopyrimidinecompounds 63 and 64, wherein X is O or S; Hal is Cl, Br, or I; and R²and R¹⁰ are as defined for Formula Ia and Ib compounds, or precursors orprodrugs thereto. An example of R¹⁰C(O)Z to prepare 6-formyl compounds(R¹⁰═H) is N,N′-dimethylformamide (DMF).

Scheme 4 shows a general method for Suzuki-type coupling of a 2-halopyrimidine intermediate (65 and 66) with a fused bicyclic heterocycle orheteroaryl boronate acid (R¹⁵═H) or ester (R¹⁵=alkyl) reagent 67 toprepare the 2-fused bicyclic heterocycle or heteroaryl (FBHy),4-morpholino thienopyrimidine and 4-morpholino fliranopyrimidinecompounds (68 and 69) of Formulas Ia and Ib wherein X is O or S; Hal isCl, Br, or I; and R¹ and R² are as defined for Formula Ia and Ibcompounds, or precursors or prodrugs thereto. For reviews of the Suzukireaction, see: Miyaura et al. (1995) Chem. Rev. 95:2457-2483; Suzuki, A.(1999) J. Organomet. Chem. 576:147-168; Suzuki, A. in Metal-CatalyzedCross-Coupling Reactions, Diederich, F., Stang, P. J., Eds., VCH,Weinheim, DE (1998), pp 49-97. The palladium catalyst may be any that istypically used for Suzuki-type cross-couplings, such as PdCl₂(PPh₃)₂,Pd(PPh₃)₄, Pd(OAc)₂, PdCl₂(dppf)-DCM, Pd₂(dba)₃/Pt—Bu)₃ (Owens et al(2003) Bioorganic & Med. Chem. Letters 13:4143-4145; Molander et al(2002) Organic Letters 4(11):1867-1870; U.S. Pat. No. 6,448,433).

Scheme 5 shows a general method for the synthesis of alkynes 71, whichcan be used to prepare alkynylated derivatives of compounds 72 and 73.Propargylic amines 71 may be prepared by reaction of propargyl bromide70 with an amine of the formula R¹⁰R¹¹NH (wherein R¹⁰ and R¹¹ areindependently selected from H, alkyl, aryl and heteroaryl, or R¹⁰ andR¹¹ together with the nitrogen to which they are attached form aheterocyclic ring) in the presence of an appropriate base (Cs₂CO₃ or thelike). For reviews of alkynyl amines and related syntheses seeBooker-Milburn, K. I., Comprehensive Organic Functional GroupTransformations (1995), 2:1039-1074; and Viehe, H. G., (1967) Angew.Chem., Int. Ed. Eng., 6(9):767-778. Alkynes 71 may subsequently bereacted with intermediates 72 (X²=bromo or iodo) or 73 (via Sonogashiracoupling), to provide compounds 74 and 75, respectively, wherein X is Oor S, and R² and R³ are as defined for Formula Ia and Ib compounds, orprecursors or prodrugs thereto.

Scheme 6 shows a general method for the synthesis of alkynes 77, whichcan be used to prepare alkynylated derivatives of compounds 72 and 73.Gem-dialkyl propargylic amines 77 may be prepared using methodsdescribed by Zaragoza, F., et al. (2004) J. Med. Chem., 47:2833.According to Scheme 10, gem-dialkyl chloride 76 (R¹⁴ and R¹⁵ areindependently methyl, ethyl or other alkyl group) can be reacted with anamine of the formula R¹⁰R¹¹NH (wherein R¹⁰ and R¹¹ are independentlyselected from H, alkyl, aryl and heteroaryl, or R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached form a heterocyclic ring)in the presence of CuCl and an appropriate base (e.g. TEA or the like)to provide the alkyne 77. Alkyne 77 can be reacted with intermediates 72or 73 (via Sonogashira coupling) to provide compounds 78 and 79,respectively, wherein X is O or S, and R² and R³ are as defined forFormula Ia and Ib compounds, or precursors or prodrugs thereto.

Scheme 7 shows a general scheme for the synthesis of alkynes 81, whichcan be used to prepare alkynylated derivatives of compounds 72 and 73.But-3-yn-1-amines 81 (wherein R¹⁴ and R¹⁵ are independently H, alkyl,aryl, heteroaryl, or R¹⁴ and R¹⁵ together with the carbon atom to whichthey are attached form a carbocyclic or heterocyclic ring) can beprepared from reaction of alkynes 80 (LG=tosylate or other leavinggroup) with an amine of the formula R¹⁰R¹¹NH (wherein R¹⁰ and R¹¹ areindependently selected from H, alkyl, aryl and heteroaryl, or R¹⁰ andR¹¹ together with the nitrogen to which they are attached form aheterocyclic ring) using the protocol described by Olomucki M. et al(1960) Ann. Chim. 5:845. Alkynes 81 can subsequently be reacted withintermediates 72 or 73 (via Sonogashira coupling), according to thedescriptions provided for Schemes 5 and 7 to provide compounds 82 and83, respectively, wherein X is O or S, and R² and R³ are as defined forFormula Ia and Ib compounds, or precursors or prodrugs thereto.

Methods of Separation

In the methods of preparing the compounds of this invention, it may beadvantageous to separate reaction products from one another and/or fromstarting materials. The desired products of each step or series of stepsis separated and/or purified (hereinafter separated) to the desireddegree of homogeneity by the techniques common in the art. Typicallysuch separations involve multiphase extraction, crystallization from asolvent or solvent mixture, distillation, sublimation, orchromatography. Chromatography can involve any number of methodsincluding, for example: reverse-phase and normal phase; size exclusion;ion exchange; high, medium and low pressure liquid chromatographymethods and apparatus; small scale analytical; simulated moving bed(SMB) and preparative thin or thick layer chromatography, as well astechniques of small scale thin layer and flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. “Stereochemistry of OrganicCompounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,(1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: “DrugStereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem.,(1982) 47:4165), of the racemic mixture, and analyzing the ¹H NMRspectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111). By method (3), a racemic mixture of two enantiomers canbe separated by chromatography using a chiral stationary phase (“ChiralLiquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, NewYork; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purifiedenantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism.

Biological Evaluation

Determination of the activity of PI3 kinase activity of a compound ofFormula Ia or Ib is possible by a number of direct and indirectdetection methods. Certain exemplary compounds described herein wereprepared, characterized, and assayed for their PI3K binding activity(Examples 364 and 365) and in vitro activity against tumor cells(Example 366). The range of PI3K binding activities was less than 1 nM(nanomolar) to about 10 μM (micromolar). Certain exemplary compounds ofthe invention had PI3K binding activity IC₅₀ values less than 10 nM.Certain compounds of the invention had tumor cell-based activity IC₅₀values less than 100 nM.

The Formula Ia and Ib compounds may inhibit p110 catalytic subunitisoforms including alpha, beta, gamma, and delta as pan inhibitors.Certain Formula Ia and Ib compounds may be p110 isoform selectiveinhibitors by selectively inhibiting one of one of the p110 isoforms;alpha, beta, gamma, or delta. One embodiment of the invention is aFormula Ia or Ib compound which is a p110 alpha selective inhibitor. Ap110 selective inhibitor may mitigate the risk of toxicity due topotential toxicities associated with inhibiting the other p110 isoforms.Certain Formula Ia and Ib compounds may be p110 isoform pan inhibitorsby possessing significant binding to two or more of the p110 isoforms.One embodiment of the invention is a Formula Ia or Ib compound which isa pan inhibitor of PI3K.

Binding of Formula Ia and Ib compounds from Tables 1a and 1b to purifiedpreparations of p110 isoforms alpha, beta, delta, and gamma was measuredby a Scintillation Proximity Assay (SPA) to determine binding activity(IC₅₀ μMol) and selectivity of binding of beta, delta, and gammaisoforms relative to alpha (Example 365). These values are expressed inTable 2.

The cytotoxic or cytostatic activity of Formula Ia and Ib exemplarycompounds was measured by: establishing a proliferating mammalian tumorcell line in a cell culture medium, adding a Formula Ia or Ib compound,culturing the cells for a period from about 6 hours to about 5 days; andmeasuring cell viability (Example 366). Cell-based in vitro assays wereused to measure viability, i.e. proliferation (IC₅₀), cytotoxicity(EC₅₀), and induction of apoptosis (caspase activation).

The in vitro potency of Formula Ia and Ib exemplary compounds wasmeasured by the cell proliferation assay, CellTiter-Glo® LuminescentCell Viability Assay, commercially available from Promega Corp.,Madison, Wis. (Example 366). This homogeneous assay method is based onthe recombinant expression of Coleoptera luciferase (U.S. Pat. Nos.5,583,024; 5,674,713; 5,700,670) and determines the number of viablecells in culture based on quantitation of the ATP present, an indicatorof metabolically active cells (Crouch et al (1993) J. Immunol. Meth.160:81-88; U.S. Pat. No. 6,602,677). The CellTiter-Glo® Assay wasconducted in 96 or 384 well format, making it amenable to automatedhigh-throughput screening (HTS) (Cree et al (1995) AntiCancer Drugs6:398-404). The homogeneous assay procedure involves adding the singlereagent (CellTiter-Glo® Reagent) directly to cells cultured inserum-supplemented medium. Cell washing, removal of medium and multiplepipetting steps are not required. The system can detect as few as 15cells/well in a 384-well format in 10 minutes after adding reagent andmixing.

The homogeneous “add-mix-measure” format results in cell lysis andgeneration of a luminescent signal proportional to the amount of ATPpresent. The amount of ATP is directly proportional to the number ofcells present in culture. The CellTiter-Glo® Assay generates a“glow-type” luminescent signal, produced by the luciferase reaction,which has a half-life generally greater than five hours, depending oncell type and medium used. Viable cells are reflected in relativeluminescence units (RLU). The substrate, Beetle Luciferin, isoxidatively decarboxylated by recombinant firefly luciferase withconcomitant conversion of ATP to AMP and generation of photons. Theextended half-life eliminates the need to use reagent injectors andprovides flexibility for continuous or batch mode processing of multipleplates. This cell proliferation assay can be used with various multiwellformats, e.g. 96 or 384 well format. Data can be recorded by luminometeror CCD camera imaging device. The luminescence output is presented asrelative light units (RLU), measured over time.

The anti-proliferative effects of Formula Ia and Ib exemplary compoundswere measured by the CellTiter-Glob Assay (Example 366) against severaltumor cell lines, including PC3, Detroit 562, and MDAMB361.1. EC₅₀values were established for the tested compounds. The range of in vitrocell potency activities was about 100 nM to about 10 μM.

Certain ADME properties were measured for certain exemplary compounds byassays including: Caco-2 Permeability (Example 367), HepatocyteClearance (Example 368), Cytochrome P450 Inhibition (Example 369),Cytochrome P450 Induction (Example 370), Plasma Protein Binding (Example371), and HERG channel blockage (Example 372).

Exemplary Formula Ia and Ib compounds No. 101-446 which were madeaccording to the methods of this invention include the followingstructures and their corresponding names (ChemDraw Ultra, CambridgeSoftCorp., Cambridge Mass.) in Tables 1a and 1b.

TABLE 1a No. Structure Name 101.

3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylbenzamide 102.

2-(1H-indazol-4-yl)-4-morpholino-6-(3-isopropylsulfonylaminophenyl)thieno[3,2- d]pyrimidine 103.

(S)-1-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)ethanol 104.

(R)-1-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)ethanol 105.

2-(1H-indazol-4-yl)-4-morpholino-6-(propylsulfonyl)thieno[2,3-d]pyrimidin 106.

2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-1-methoxypropan-2-ol 107.

2-(2-(1H-indazol-4-yl)-4- morpholinofuro[3,2-d]pyrimidin-6-yl)propan-2-ol 108.

2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-1,3-dimethoxypropan-2-ol 109.

2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-1-(diethylamino)propan-2-ol 110.

1-(4-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)ethanone 111.

2-(1H-indazol-4-yl)-6-(3- (methylsulfonyl)phenyl)-4-morpholinofuro[3,2-d]pyrimidine 112.

N-(3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxy-2-methylpropanamide 113.

(2S)-N-(3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxypropanamide 114.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6- yl)methanol115.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 116.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methan(methylsulfonyl)amine 117.

2-(1H-indazol-4-yl)-4-morpholino-N-(pyridin-3-yl)thieno[3,2-d]pyrimidin-6- amine 118.

2-(4-(2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)ethyl)piperazin-1-yl)-N,N- dimethylacetamide 119.

N-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-2-methoxyacetamide 120.

N-(3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-methoxyacetamide 121.

2-(1H-indazol-4-yl)-4-morpholino-N-(pyridin-2-yl)thieno[3,2-d]pyrimidin-6- amine 122.

(2-(1H-indazol-4-yl)-4- morpholinothieno[2,3-d]pyrimidin-6-yl)(4-methylpiperazin-1-yl)methanone 123.

(2-(1H-indazol-4-yl)-4- morpholinothieno[2,3-d]pyrimidin-6-yl)(4-hydroxypiperidin-1-yl)methanone 124.

(2-(1H-indazol-4-yl)-4- morpholinothieno[2,3-d]pyrimidin-6-yl)(4-acetylpiperazin-1-yl)methanone 125.

(2-(1H-indazol-4-yl)-4- morpholinothieno[2,3-d]pyrimidin-6-yl)(4-methylsulfonylpiperazin-1-yl)methanone 126.

2-(1H-indazol-4-yl)-N-isopropyl-4- morpholinothieno[2,3-d]pyrimidine-6-carboxamide 127.

N-(2,2,2-trifluoroethyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6- carboxamide 128.

N-(2-hydroxyethyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6- carboxamide 129.

N-ethyl-2-(1H-indazol-4-yl)-4- morpholinothieno[2,3-d]pyrimidine-6-carboxamide 130.

2-(1H-indazol-4-yl)-N,N-dimethyl-4- morpholinothieno[2,3-d]pyrimidine-6-carboxamide 131.

2-(1H-indazol-4-yl)-N-methyl-4- morpholinothieno[2,3-d]pyrimidine-6-carboxamide 132.

4-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-tetrahydro-2H-thiopyran-4-ol 133.

1-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)cyclobutanol 134.

6-chloro-2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidine 135.

(R)-1-(3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)phenylsulfonyl)propan-2-ol 136.

N-(3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-amino-2-methylpropanamide 137.

N-(3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-aminoacetamide 138.

(S)-1-(3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)phenylsulfonyl)propan-2-ol 139.

N-(3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxyacetamide 140.

2-(2-(1H-indazol-4-yl)-4- morpholinothieno[2,3-d]pyrimidin-6-yl)propan-2-ol 141.

2-(1H-indazol-4-yl)-4-morpholinothieno[2,3- d]pyrimidine-6-carboxylicacid 142.

2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine-6-carboxamide143.

6-((3-methoxypropylsulfonyl)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 144.

2-(1H-indazol-4-yl)-4-morpholino-6-(2-(4- methylsulfonylpiperazin-1-yl)ethyl)thieno[3,2-d]pyrimidine 145.

3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylpropanamide 146.

2-(1H-indazol-4-yl)-6- ((methylsulfonyl)methyl)-4-morpholinothieno[3,2-d]pyrimidine 147.

3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)propanamide 148.

3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-N,N-dimethylpropanamide 149.

3-(2-(1H-indazol-4-yl)-4- morpholinothieno[2,3-d]pyrimidin-6-yl)-1-(4-methylsulfonylpiperazin-1-yl)propanone 150.

2-(1H-indazol-4-yl)-4-morpholino-N- phenylthieno[3,2-d]pyrimidin-6-amine151.

3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)benzenmethylsulfonamide 152.

N-(3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-(dimethylamino)acetamide 153.

2-(1H-indazol-4-yl)-6-(3-methoxypyridin-4-yl)-4-morpholinothieno[3,2-d]pyrimidine 154.

3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)pentan-3-ol 155.

6-(6-fluoropyridin-3-yl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine 156.

6-(2-fluoropyridin-3-yl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine 157.

2-(1H-indazol-4-yl)-6-(4-methoxypyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidine 158.

3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine 159.

2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)benzamide 160.

N-(2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)acetamide 161.

3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)benzamide 162.

N-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)propionamide 163.

N-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)acetamide 164.

N-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)isobutyramide 165.

N-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)benzamide 166.

3-(1H-indazol-4-yl)-4-morpholino-6-(2-(4- methylsulfonylpiperazin-1-yl)propyl)thieno[3,2-d]pyrimidine 167.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)(4-(methylacetamido)piperidin-1-yl)methanone 168.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)(3-(methylsulfonyl)pyrrolidin-1-yl)methanone 169.

2-(1H-indazol-4-yl)-N-(2- (methylsulfonyl)ethyl)-4-morpholinothieno[3,2-d]pyrimidine-6- carboxamide 170.

N-ethyl-2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidine-6-carboxamide 171.

2-(1H-indazol-4-yl)-N-methyl-4- morpholinothieno[3,2-d]pyrimidine-6-carboxamide 172.

N-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)cyclopropanecarboxamide 173.

N-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-3,3-dimethylbutanamide 174.

2-(2-methyl-1H-benzo[d]imidazol-1-yl)-4-morpholinothieno[3,2-d]pyrimidine 175.

2-(1H-indazol-4-yl)-6-(3-(4- methylpiperazin-1-yl)prop-1-ynyl)-4-morpholinothieno[3,2-d]pyrimidine 176.

2-(1H-indazol-4-yl)-4-morpholino-6-(3-(pyrrolidin-1-yl)prop-1-ynyl)thieno[3,2- d]pyrimidine 177.

2-(1H-indazol-4-yl)-4-morpholino-6-(3- morpholinoprop-1-ynyl)thieno[3,2-d]pyrimidine 178.

2-(1H-indazol-4-yl)-4-morpholino-6-(3-(4-methylsulfonylpiperazin-1-yl)thieno[3,2- d]pyrimidine 179.

(2-(1H-indol-4-yl)-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methanol180.

2-(1H-indazol-4-yl)-6-((1-methylpiperidin-4-yl)methyl)-4-morpholinothieno[3,2- d]pyrimidine 181.

2-(1H-indazol-4-yl)-6-((1-methylpiperidin-4-ylidene)methyl)-4-morpholinothieno[3,2- d]pyrimidine 182.

2-(1H-indazol-4-yl)-6-(4-methoxy-1- methylpiperidin-4-yl)-4-morpholinothieno[3,2-d]pyrimidine 183.

4-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-1-methylpiperidin-4-ol 184.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-N-sulfonylmethyl-N-(2- morpholinoethyl)methanamine 185.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylsulfonyl-N-(2-N,N- dimethylaminoethyl)methanamine 186.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methyl,N-(3- morpholinopropylsulfonyl)methanamine 187.

(2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methyl,N-(3- morpholinopropylsulfonyl)methanamine188.

2-(1H-indazol-4-yl)-N-(2-methoxyethyl)-4-morpholinothieno[3,2-d]pyrimidine-6- carboxamide 189.

2-(1H-indol-4-yl)-N-(2-methoxyethyl)-4-morpholinothieno[3,2-d]pyrimidine-6- carboxamide 190.

(2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methyl-N-(2-N,N- dimethylaminosulfonyl)methanamine191.

2-(1H-indol-4-yl)-6-(2- (methylsulfonyl)ethyl)-4-morpholinothieno[3,2-d]pyrimidine 192.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-methylacetamide 193.

N-((2-(1H-indol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-methylacetamide 194.

N-((2-(1H-indol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-(methyl)methylsulfonamide 195.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-methylsulfonyl-1- methylpyrrolidin-3-amine 196.

2-(1H-indazol-4-yl)-6-(3-((4- methylsulfonylpiperazin-1-yl)methyl)phenyl)-4-morpholinothieno[3,2- d]pyrimidine 197.

2-(1H-indazol-4-yl)-6-(3-((4- methylpiperazin-1-yl)methyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidine 198.

4-(4-morpholinothieno[3,2-d]pyrimidin-2- yl)indolin-2-one 199.

2-(1H-indol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 200.

2-(1H-indazol-4-yl)-4-morpholino-6-(pyrimidin-5-yl)thieno[3,2-d]pyrimidine 201.

2-(1H-indazol-4-yl)-4-morpholino-6- phenylfuro[3,2-d]pyrimidine 202.

N-(cyclopropylmethoxy)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6- carboxamide 203.

2-(1H-indazol-4-yl)-4-morpholino-6-(1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine 204.

2-(1H-indazol-4-yl)-4-morpholino-6- phenylthieno[3,2-d]pyrimidine 205.

(S)-1-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)propan-2-ol 206.

2-(1H-indazol-4-yl)-N-(methylsulfonyl)-4-morpholinothieno[3,2-d]pyrimidine-6- carboxamide 207.

6-(isobutylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine 208.

6-(3-hydroxyphenylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 209.

6-((4-piperazin-2-one)sulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 210.

6-(4-methylpiperazinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 211.

6-(2-hydroxymethylpiperidinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 212.

6-(3-hydroxymethylpiperidinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 213.

6-(4-hydroxymethylpiperidinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 214.

6-(4-(2-hydroxyethyl)piperidinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 215.

6-(4-(2-hydroxyethyl)piperazinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 216.

6-(4-hydroxypiperidinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 217.

6-(3-hydroxypyrrolidinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 218.

6-(2-piperidinylethylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 219.

6-(2-N-morpholinoethylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 220.

6-(3-methoxypropylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 221.

6-(N,N-bis-2-hydroxyethylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 222.

6-(2-hydroxyethylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 223.

6-(dimethylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine 224.

6-(methylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine 225.

2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidin-6-amine 226.

2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-ylamino)ethanol 227.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-N-sulfonylmethyl-N-(2- methoxyethyl)methanamine 228.

1-(4-(4-morpholinothieno[3,2-d]pyrimidin-2- yl)indolin-1-yl)ethanone229.

2-(1H-indazol-6-yl)-4-morpholinothieno[3,2- d]pyrimidine 230.

4-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-1-((thiazol-2-yl)methyl)piperidin-4-ol 231.

4-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-1-(methylsulfonyl)piperidin-4-ol 232.

4-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-1-((pyridin-2-yl)methyl)piperidin-4-ol 233.

2-(1H-indazol-4-yl)-4-morpholino-6- phenylfuro[3,2-d]pyrimidine 234.

2-(1H-indazol-4-yl)-6-(methylsulfonyl)-4-morpholinothieno[3,2-d]pyrimidine 235.

2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol 236.

2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine-6-(N-phenylsulfonyl)carboxamide 237.

(3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)methanol 238.

N-(3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)acetamide 239.

2-(1H-indazol-4-yl)-4-morpholino-6-(pyridin-4-yl)thieno[3,2-d]pyrimidine 240.

2-(1H-indazol-4-yl)-4-morpholino-6-(pyridin-3-yl)thieno[3,2-d]pyrimidine 241.

2-(1H-indazol-4-yl)-6-(3,4- dimethoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidine 242.

2-(1H-indazol-4-yl)-4-morpholino-6-(4-acetyl-piperazinosulfonyl)thieno[3,2- d]pyrimidine 243.

2-(1H-indazol-4-yl)-4-morpholino-6-(4- methylsulfonyl-piperazinosulfonyl)thieno[3,2-d]pyrimidine 244.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone 245.

N-benzyl-2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidine-6-carboxamide 246.

N-(3-hydroxyphenyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6- carboxamide 247.

2-(1H-indazol-4-yl)-4-morpholino-N- phenylthieno[3,2-d]pyrimidine-6-carboxamide 248.

N-((dimethylcarbamoyl)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine-6-carboxamide 249.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone 250.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)(piperazin-2-one)methanone 251.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)(4-hydroxypiperidin-1-yl)methanone 252.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)(morpholino)methanone 253.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)(3-(methylamino)pyrrolidin-1-yl)methanone 254.

N-(2,2,2-trifluoroethyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6- carboxamide 255.

2-(1H-indazol-4-yl)-4-morpholino-N-(2-morpholinoethyl)thieno[3,2-d]pyrimidine-6- carboxamide 256.

2-(1H-indazol-4-yl)-N-isobutyl-4- morpholinothieno[3,2-d]pyrimidine-6-carboxamide 257.

2-(1H-indazol-4-yl)-4-morpholino-N-(2- (piperidin-1-yl)ethyl)thieno[3,2-d]pyrimidine-6-carboxamide 258.

N,N-bis(2-hydroxyethyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6- carboxamide 259.

2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6- yl)ethanol260.

N-(1-hydroxypropan-2-yl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6- carboxamide 261.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)(4-methylpiperazin-1-yl)methanone 262.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)(4-methylsulfonylpiperazin-1-yl)methanone 263.

2-(1H-indazol-4-yl)-N,N-dimethyl-4- morpholinothieno[3,2-d]pyrimidine-6-carboxamide 264.

2-(1H-indazol-4-yl)-6-(4- (methylsulfonyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidine 265.

2-(1H-indazol-4-yl)-6-(3- (methylsulfonyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidine 266.

N-(2-hydroxyethyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6- carboxamide 267.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)(4-acetylpiperazin-1-yl)methanone 268.

(4-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)methanol 269.

1-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-2-methylpropan-2-ol 270.

2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 271.

2-(1H-indol-5-yl)-4-morpholinothieno[3,2- d]pyrimidine 272.

2-(1H-indol-6-yl)-4-morpholinothieno[3,2- d]pyrimidine 273.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-(methyl)methylsulfonamide 274.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)acetamide 275.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)benzamide 276.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)picolinamide 277.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)nicotinamide 278.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)isonicotinamide 279.

3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-1-(4-methylpiperazin-1-yl)propan-1-one 280.

2-(1H-indazol-4-yl)-6-(methoxymethyl)-4-morpholinothieno[3,2-d]pyrimidine 281.

6-((benzyloxy)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine 282.

6-(((pyridin-2-yl)methoxy)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 283.

6-(((pyridin-3-yl)methoxy)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 284.

6-(((pyridin-4-yl)methoxy)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 285.

2-(1H-indazol-4-yl)-4-morpholino-6-(phenoxymethyl)thieno[3,2-d]pyrimidine

TABLE 1b Example Structure Name 286.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)benzamide 287.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)picolinamide 288.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)nicotinamide 289.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)acetamide 290.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)isonicotinamide 291.

2-(1H-indazol-4-yl)-4- morpholinofuro[3,2- d]pyrimidine-6-carboxamide292.

(2-(1H-indazol-4-yl)-4- morpholinofuro[3,2-d]pyrimidin- 6-yl)(4-N-methylsulfonylpiperazin-1- yl)methanone 293.

2-(1H-indazol-4-yl)-N-methyl-4- morpholinofuro[3,2-d]pyrimidine-6-carboxamide 294.

(S)-1-(2-(1H-indazol-4-yl)-4- morpholinofuro[3,2-d]pyrimidin-6-yl)ethanol 295.

(R)-1-(2-(1H-indazol-4-yl)-4- morpholinofuro[3,2-d]pyrimidin-6-yl)ethanol 296.

(2-(1H-indazol-4-yl)-4- morpholinofuro[3,2-d]pyrimidin- 6-yl)methanol297.

2-(1H-indazol-4-yl)-6-(4- methoxypyridin-3-yl)-4-morpholinofuro[3,2-d]pyrimidine 298.

2-(1H-indazol-4-yl)-4- morpholinothieno[2,3- d]pyrimidine-6-carboxamide299.

2-(1H-indazol-4-yl)-4- morpholino-6-(3- (morpholinomethyl)phenyl)thieno[3,2-d]pyrimidine 300.

methyl 3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-5- aminobenzoate 301.

N-(3-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)methylamino)phenyl)acetamide 302.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)benzenamine 303.

3-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)methylamino)benzamide 304.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)-N,N-dimethylmethanamine 305.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)morpholine-4- carboxamide 306.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)N-phenylsulfonylmethanamine 307.

3-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1,1- dimethylurea 308.

1-(2-(1H-indazol-4-yl)-4- morpholinothieno[2,3- d]pyrimidin-6-yl)ethanol309.

2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)sulfonamide 310.

2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-amine 311.

3-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)oxazolidin-2-one 312.

6-((1H-imidazol-1-yl)methyl)-2- (1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 313.

6-((1H-1,2,4-triazol-1-yl)methyl)- 2-(1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 314.

2-(1H-indazol-4-yl)-6- (methoxymethyl)-4-morpholinothieno[3,2-d]pyrimidine 315.

6-((benzyloxy)methyl)-2-(1H- indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidine 316.

2-(1H-indazol-4-yl)-4- morpholino-6- (phenoxymethyl)thieno[3,2-d]pyrimidine 317.

6-(((pyridin-2- yl)methoxy)methyl)-2-(1H- indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 318.

4-morpholino-2-(1H-pyrrolo[2,3- b]pyridin-5-yl)-7-(thiazol-5-yl)thieno[3,2-d]pyrimidine 319.

6-(((pyridin-3- yl)methoxy)methyl)-2-(1H- indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 320.

6-(((pyridin-4- yl)methoxy)methyl)-2-(1H- indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 321.

2-(2-(1H-indol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol 322.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2- hydroxy-2-methylpropanamide 323.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2- hydroxyacetamide 324.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3- (methylsulfonyl)benzamide 325.

6-((1H-pyrazol-1-yl)methyl)-2- (1H-indazol-4-yl)-4-morpholinothieno[3,2- d]pyrimidine 326.

1-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1H- benzo[d]imidazol-2(3H)-one 327.

3-(2-(1H-indazol-4-yl)-4- morpholinofuro[3,2-d]pyrimidin- 6-yl)-N-methylsulfonylbenzenamine 328.

2-(1H-indazol-4-yl)-6-(isoxazol- 4-yl)-4-morpholinothieno[3,2-d]pyrimidine 329.

3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)-N-ethylbenzamide 330.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-(N- methylsulfonylamino)acetamide 331.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2- aminoacetamide 332.

2-(1H-indazol-4-yl)-4- morpholino-6-(1-(4-N- methylsulfonylpiperazin-1-yl)ethyl)thieno[3,2-d]pyrimidine 333.

2-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methoxy)-N,N- dimethylacetamide 334.

2-(1H-indazol-4-yl)-6-((E)-3- methoxyprop-1-enyl)-4-morpholinothieno[3,2- d]pyrimidine 335.

2-(1H-indazol-4-yl)-6-(3- methoxyphenyl)-4- morpholinothieno[3,2-d]pyrimidine 336.

3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2- hydroxypropyl)benzamide 337.

(3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)phenyl)(morpholino)methanone 338.

3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)benzoicacid 339.

(3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)(4- methylpiperazin-1-yl)methanone 340.

3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)-N-(2-(dimethylamino)ethyl)benzamide 341.

N-(3-(2-(1H-indazol-4-yl)-4- morpholinofuro[3,2-d]pyrimidin-6-yl)phenyl)acetamide 342.

5-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2- hydroxypropyl)pyridine-3- carboxamide 343.

5-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)-N-(2-(dimethylamino)ethyl)pyridine-3- carboxamide 344.

5-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)-N-methylpyridine-3-carboxamide 345.

2-(2-(1H-indol-6-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol 346.

2-(4-morpholino-2-(quinolin-3- yl)thieno[3,2-d]pyrimidin-6-yl)propan-2-ol 347.

(5-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)pyridin-3- yl)(morpholino)methanone 348.

(5-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)pyridin-3-yl)(4- methylpiperazin-1-yl)methanone 349.

5-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3- carboxylic acid 350.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2- (dimethylamino)acetamide 351.

2-(4-morpholino-2-(1H- pyrrolo[2,3-b]pyridin-5-yl)thieno[2,3-d]pyrimidin-6- yl)propan-2-ol 352.

N-(3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-N- methylacetamide 353.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)(4-N-methylsulfonylpiperidin-4- yl)methanol 354.

1-(2-(1H-indazol-4-yl)-4- morpholinofuro[3,2-d]pyrimidin- 6-yl)ethanol355.

2-(1H-indazol-4-yl)-4- morpholino-6-((pyridin-3-yloxy)methyl)thieno[3,2- d]pyrimidine 356.

7-methyl-6-(5- (methylsulfonyl)pyridin-3-yl)-4-morpholino-2-(1H-pyrrolo[2,3- b]pyridin-5-yl)thieno[3,2- d]pyrimidine357.

6-((hexahydro-2- methylsulfonylpyrrolo[3,4-c]pyrrol-5(1H)-yl)methyl)-2-(1H- indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidine 358.

3-(2-(1H-indazol-4-yl)-7-methyl- 4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N- methylbenzamide 359.

N-(3-(2-(1H-indazol-4-yl)-7- methyl-4-morpholinothieno[3,2-d]pyrimidin-6- yl)phenyl)acetamide 360.

2-(1H-indazol-4-yl)-7-methyl-6- (3-(methylsulfonyl)phenyl)-4-morpholinothieno[3,2- d]pyrimidine 361.

2-(1H-indazol-4-yl)-6-(4- methoxypyridin-3-yl)-7-methyl-4-morpholinothieno[3,2- d]pyrimidine 362.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3- methoxybenzamide 363.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4- methoxybenzamide 364.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4- methoxybenzenamine 365.

2-(1H-indazol-4-yl)-6-((2-methyl- 1H-imidazol-1-yl)methyl)-4-morpholinothieno[3,2- d]pyrimidine 366.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2- methoxybenzenamine 367.

3-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)- N-methylbenzamide 368.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-6- methoxypyridin-3-amine 369.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)pyridin- 3-amine 370.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4- morpholinobenzenamine 371.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1H- pyrazol-5-amine 372.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1,3- dihydrobenzo[c]thiopen-1,1-dioxide-5-amine 373.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-6- morpholinopyridin-3-amine 374.

N1-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3- methylsulfonylaminobenzene-1- amine 375.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3- (methylsulfonyl)benzenamine 376.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)-N-cyclopropylsulfonylmethanamine 377.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-(3- methoxyphenyl)acetamide 378.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-(4- methoxyphenyl)acetamide 379.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)-N-methylsulfonylmethanamine 380.

2-(N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N- bis-(N-cyclopropylacetamide)- methanamine381.

1-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N- methylsulfonylazetidin-3-amine 382.

2-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)- N-cyclopropylacetamide 383.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2- (methylsulfonyl)ethanamine 384.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3- (methylsulfonyl)propan-1-amine 385.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3- (dimethylaminosulfonyl)propan- 1-amine 386.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N- methyl(phenyl)methanamine 387.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(3- methoxyphenyl)-N- methylmethanamine 388.

N-(2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2- yl)benzamide 389.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)-N-methylmethanamine 390.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N- methylbenzamide 391.

N-((2-(1H-indazol-4-yl)-7- methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N- methylsulfonyl-methanamine 392.

N-((2-(1H-indol-5-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N- methylacetamide 393.

N-(3-(2-(1H-indazol-4-yl)-4- morpholinothieno[2,3- d]pyrimidin-6-yl)phenyl)acetamide 394.

2-(1H-indazol-4-yl)-6-(3- (methylsulfonyl)phenyl)-4-morpholinothieno[2,3- d]pyrimidine 395.

7-methyl-6-(3- (methylsulfonyl)phenyl)-4- morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2- d]pyrimidine 396.

2-(1H-indazol-4-yl)-6-(4- methoxypyridin-3-yl)-4- morpholinothieno[2,3-d]pyrimidine 397.

2-(1H-indazol-4-yl)-6-(1H-indol- 4-yl)-4-morpholinothieno[3,2-d]pyrimidine 398.

2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)-N-methylsulfonylpropan-2-amine 399.

N-(2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2- yl)acetamide 400.

2-(1H-indazol-4-yl)-4- morpholino-6-(6- morpholinopyridin-3-yl)thieno[3,2-d]pyrimidine 401.

2-(1H-indazol-4-yl)-6-(2-(4-N- methylsulfonylpiperazin-1-yl)propan-2-yl)-4- morpholinothieno[3,2- d]pyrimidine 402.

2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidine-6-carbonitrile403.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2- methoxy-N-methylacetamide 404.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)(4-(methylthio)phenyl)methanol 405.

(2-(1H-indazol-4-yl)-4- morpholinothieno[2,3- d]pyrimidin-6-yl)-N-methylsulfonyl,N- methylmethanamine 406.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N- methylacetamide 407.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2- hydroxy-N,2- dimethylpropanamide 408.

N-((2-(1H-indazol-4-yl)-7- methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N- methylacetamide 409.

N-((2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2- hydroxy-N-methylacetamide 410.

N-(2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2- yl)nicotinamide 411.

N-(2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-yl)-3- methoxybenzamide 412.

N-(2-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-yl)-4- methoxybenzamide 413.

(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2- d]pyrimidin-6-yl)(4-(methylsulfonyl)phenyl)methanol 414.

2-(2-(2-methyl-3H-imidazo[4,5- b]pyridin-6-yl)-4- morpholinothieno[2,3-d]pyrimidin-6-yl)propan-2-ol 415.

(S)-1-(3-(7-methyl-4-morpholino- 2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6- yl)phenylsulfonyl)propan-2-ol 416.

7-methyl-6-(3-(N- morpholino)sulfonyl)phenyl)-4-morpholino-2-(1H-pyrrolo [2,3- b]pyridin-5-yl)thieno[3,2- d]pyrimidine417.

N-methyl,N-methylsulfonyl(4- morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[2,3- d]pyrimidin-6-yl)methanamine 418.

6-(3-(methylsulfonyl)phenyl)-4- morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2- d]pyrimidine 419.

4-morpholino-6-phenyl-2-(1H- pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidine 420.

7-methyl-4-morpholino-6-phenyl- 2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidine 421.

(2S)-2-hydroxy-N-((3-(7-methyl- 4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2- d]pyrimidin-6- yl)phenyl)methyl)propanamide422.

2-(4-morpholino-2-(1H- pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6- yl)propan-2-ol 423.

7-methyl-6-(3-(2- hydroxyethylaminosulfonyl)phenyl)- 4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5- yl)thieno[3,2-d]pyrimidine 424.

N-methylsulfonyl(3-(7-methyl-4- morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2- d]pyrimidin-6- yl)phenyl)methanamine 425.

(4-hydroxypiperidin-1-yl)(3-(7- methyl-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5- yl)thieno[3,2-d]pyrimidin-6-yl)phenyl)methanone 426.

N-(2-hydroxyethyl)-3-(7-methyl- 4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2- d]pyrimidin-6-yl)benzamide 427.

(3-(7-methyl-4-morpholino-2- (1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6- yl)phenyl)(4-methylpiperazin-1-yl)methanone 428.

4-morpholino-6-(6- morpholinopyridin-3-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5- yl)thieno[3,2-d]pyrimidine 429.

4-(4-morpholino-2-(1H- pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6- yl)thiazol-2-amine 430.

6-(7-methyl-6-(3- (methylsulfonyl)phenyl)-4- morpholinothieno[3,2-d]pyrimidin-2-yl)-3H- imidazo[4,5-b]pyridine 431.

2-(2-(1H-imidazo[4,5-b]pyridin- 6-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol 432.

2-methyl-6-(7-methyl-6-(3- (methylsulfonyl)phenyl)-4-morpholinothieno[3,2- d]pyrimidin-2-yl)-3H- imidazo[4,5-b]pyridine 433.

2-(2-(2-methyl-3H-imidazo[4,5- b]pyridin-6-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol 434.

5-(7-methyl-4-morpholino-2-(1H- pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6-yl)- N-(2-morpholinoethyl)pyridin-2- amine435.

3-(5-(7-methyl-4-morpholino-2- (1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6- yl)pyridin-2-ylamino)propane- 1,2-diol 436.

2-(2-(5-(7-methyl-4-morpholino- 2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6- yl)pyridin-2- ylamino)ethoxy)ethanol 437.

N-methyl(4-morpholino-2-(1H- pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6- yl)methanamine 438.

1-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)pyrrolidin-2-one 439.

3-(2-(1H-indazol-4-yl)-4- morpholinothieno[3,2-d]pyrimidin-6-yl)oxazolidin-2- one 440.

2-(4-morpholino-2-(1H- pyrrolo[2,3-b]pyridin-5-yl)thieno[2,3-d]pyrimidin-6- yl)propan-2-ol 441.

(4-methylpiperazin-1-yl)(3-(4- morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[2,3- d]pyrimidin-6- yl)phenyl)methanone 442.

2-(2-(2-methyl-3H-imidazo[4,5- b]pyridin-6-yl)-4- morpholinothieno[2,3-d]pyrimidin-6-yl)propan-2-ol 443.

N-(3-(4-morpholino-2-(1H- pyrrolo[2,3-b]pyridin-5-yl)thieno[2,3-d]pyrimidin-6- yl)benzyl)methanesulfonamide 444.

N-(2-(dimethylamino)ethyl)-N- ((4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5- yl)thieno[2,3-d]pyrimidin-6-yl)methyl)methanesulfonamide 445.

2-(4-morpholino-2-(quinolin-3- yl)thieno[2,3-d]pyrimidin-6-yl)propan-2-ol 446.

4-(6-(3-(methylsulfonyl)phenyl)- 2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[2,3-d]pyrimidin-4- yl)morpholine

Administration of compounds of formula Ia and Ib

The compounds of the invention may be administered by any routeappropriate to the condition to be treated. Suitable routes includeoral, parenteral (including subcutaneous, intramuscular, intravenous,intraarterial, intradermal, intrathecal and epidural), transdermal,rectal, nasal, topical (including buccal and sublingual), vaginal,intraperitoneal, intrapulmonary and intranasal. For localimmunosuppressive treatment, the compounds may be administered byintralesional administration, including perfusing or otherwisecontacting the graft with the inhibitor before transplantation. It willbe appreciated that the preferred route may vary with for example thecondition of the recipient. Where the compound is administered orally,it may be formulated as a pill, capsule, tablet, etc. with apharmaceutically acceptable carrier or excipient. Where the compound isadministered parenterally, it may be formulated with a pharmaceuticallyacceptable parenteral vehicle and in a unit dosage injectable form, asdetailed below.

A dose to treat human patients may range from about 10 mg to about 1000mg of Formula Ia or Ib compound. A typical dose may be about 100 mg toabout 300 mg of the compound. A dose may be administered once a day(QID), twice per day (BID), or more frequently, depending on thepharmacokinetic and pharmacodynamic properties, including absorption,distribution, metabolism, and excretion of the particular compound. Inaddition, toxicity factors may influence the dosage and administrationregimen. When administered orally, the pill, capsule, or tablet may beingested daily or less frequently for a specified period of time. Theregimen may be repeated for a number of cycles of therapy.

Methods of Treatment with Formula Ia and Ib Compounds

Compounds of the present invention are useful for treating diseases,conditions and/or disorders including, but not limited to, thosecharacterized by over expression of lipid kinases, e.g. PI3 kinase.Accordingly, another aspect of this invention includes methods oftreating or preventing diseases or conditions that can be treated orprevented by inhibiting lipid kinases, including PI3. In one embodiment,the method comprises administering to a mammal in need thereof atherapeutically effective amount of a compound of Formula Ia or Ib, or astereoisomer, geometric isomer, tautomer, solvate, metabolite, orpharmaceutically acceptable salt or prodrug thereof.

Diseases and conditions treatable according to the methods of thisinvention include, but are not limited to, cancer, stroke, diabetes,hepatomegaly, cardiovascular disease, Alzheimer's disease, cysticfibrosis, viral disease, autoimmune diseases, atherosclerosis,restenosis, psoriasis, allergic disorders, inflammation, neurologicaldisorders, a hormone-related disease, conditions associated with organtransplantation, immunodeficiency disorders, destructive bone disorders,proliferative disorders, infectious diseases, conditions associated withcell death, thrombin-induced platelet aggregation, chronic myelogenousleukemia (CML), liver disease, pathologic immune conditions involving Tcell activation, and CNS disorders in a patient. In one embodiment, ahuman patient is treated with a compound of Formula Ia or Ib and apharmaceutically acceptable carrier, adjuvant, or vehicle, wherein saidcompound of Formula Ia or Ib is present in an amount to detectablyinhibit PI3 kinase activity.

Cancers which can be treated according to the methods of this inventioninclude, but are not limited to, breast, ovary, cervix, prostate,testis, genitourinary tract, esophagus, larynx, glioblastoma,neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoidcarcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC),small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma,pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccalcavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine,colon-rectum, large intestine, rectum, brain and central nervous system,Hodgkin's and leukemia.

Cardiovascular diseases which can be treated according to the methods ofthis invention include, but are not limited to, restenosis,cardiomegaly, atherosclerosis, myocardial infarction, and congestiveheart failure.

Neurodegenerative disease which can be treated according to the methodsof this invention include, but are not limited to, Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis, Huntington'sdisease, and cerebral ischemia, and neurodegenerative disease caused bytraumatic injury, glutamate neurotoxicity and hypoxia.

Inflammatory diseases which can be treated according to the methods ofthis invention include, but are not limited to, rheumatoid arthritis,psoriasis, contact dermatitis, and delayed hypersensitivity reactions.

Another aspect of this invention provides a compound of this inventionfor use in the treatment of the diseases or conditions described hereinin a mammal, for example, a human, suffering from such disease orcondition. Also provided is the use of a compound of this invention inthe preparation of a medicament for the treatment of the diseases andconditions described herein in a warm-blooded animal, such as a mammal,for example a human, suffering from such disorder.

Pharmaceutical Formulations

In order to use a compound of this invention for the therapeutictreatment (including prophylactic treatment) of mammals includinghumans, it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition. According tothis aspect of the invention there is provided a pharmaceuticalcomposition comprising a compound of this invention in association witha pharmaceutically acceptable diluent or carrier.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. Suitable carriers,diluents and excipients are well known to those skilled in the art andinclude materials such as carbohydrates, waxes, water soluble and/orswellable polymers, hydrophilic or hydrophobic materials, gelatin, oils,solvents, water and the like. The particular carrier, diluent orexcipient used will depend upon the means and purpose for which thecompound of the present invention is being applied. Solvents aregenerally selected based on solvents recognized by persons skilled inthe art as safe (GRAS) to be administered to a mammal. In general, safesolvents are non-toxic aqueous solvents such as water and othernon-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the compound (e.g.,complex with a cyclodextrin derivative or other known complexationagent) is dissolved in a suitable solvent in the presence of one or moreof the excipients described above. The compound of the present inventionis typically formulated into pharmaceutical dosage forms to provide aneasily controllable dosage of the drug and to enable patient compliancewith the prescribed regimen.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

Pharmaceutical formulations of the compounds of the present inventionmay be prepared for various routes and types of administration. Forexample, a compound of Formula Ia or Ib having the desired degree ofpurity may optionally be mixed with pharmaceutically acceptablediluents, carriers, excipients or stabilizers (Remington'sPharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.), in the formof a lyophilized formulation, milled powder, or an aqueous solution.Formulation may be conducted by mixing at ambient temperature at theappropriate pH, and at the desired degree of purity, withphysiologically acceptable carriers, i.e., carriers that are non-toxicto recipients at the dosages and concentrations employed. The pH of theformulation depends mainly on the particular use and the concentrationof compound, but may range from about 3 to about 8. Formulation in anacetate buffer at pH 5 is a suitable embodiment.

The compound of this invention for use herein is preferably sterile. Inparticular, formulations to be used for in vivo administration must besterile. Such sterilization is readily accomplished by filtrationthrough sterile filtration membranes.

The compound ordinarily can be stored as a solid composition, alyophilized formulation or as an aqueous solution.

The pharmaceutical compositions of the invention will be formulated,dosed and administered in a fashion, i.e., amounts, concentrations,schedules, course, vehicles and route of administration, consistent withgood medical practice. Factors for consideration in this context includethe particular disorder being treated, the particular mammal beingtreated, the clinical condition of the individual patient, the cause ofthe disorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners. The “therapeutically effective amount”of the compound to be administered will be governed by suchconsiderations, and is the minimum amount necessary to prevent,ameliorate, or treat the coagulation factor mediated disorder. Suchamount is preferably below the amount that is toxic to the host orrenders the host significantly more susceptible to bleeding.

As a general proposition, the initial pharmaceutically effective amountof the inhibitor administered parenterally per dose will be in the rangeof about 0.01-100 mg/kg, namely about 0.1 to 20 mg/kg of patient bodyweight per day, with the typical initial range of compound used being0.3 to 15 mg/kg/day.

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Theactive pharmaceutical ingredients may also be entrapped in microcapsulesprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release preparations of compounds of Formula Ia and Ib may beprepared. Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of Formula Ia or Ib, which matrices are in the form of shapedarticles, e.g., films, or microcapsules. Examples of sustained-releasematrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid.

The formulations include those suitable for the administration routesdetailed herein. The formulations may conveniently be presented in unitdosage form, and may be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.).Such methods include the step of bringing into association the activeingredient with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product.

Formulations of a compound of Formula Ia or Ib suitable for oraladministration may be prepared as discrete units such as pills,capsules, cachets or tablets each containing a predetermined amount of acompound of Formula Ia or Ib.

Compressed tablets may be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs may be prepared for oral use. Formulationsof compounds of Formula Ia or Ib intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a palatablepreparation. Tablets containing the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipient which are suitable formanufacture of tablets are acceptable. These excipients may be, forexample, inert diluents, such as calcium or sodium carbonate, lactose,calcium or sodium phosphate; granulating and disintegrating agents, suchas maize starch, or alginic acid; binding agents, such as starch,gelatin or acacia; and lubricating agents, such as magnesium stearate,stearic acid or talc. Tablets may be uncoated or may be coated by knowntechniques including microencapsulation to delay disintegration andadsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate alone or with a wax may beemployed.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w. When formulated in an ointment, the active ingredientsmay be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients may be formulated in a creamwith an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include a polyhydricalcohol, i.e., an alcohol having two or more hydroxyl groups such aspropylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol andpolyethylene glycol (including PEG 400) and mixtures thereof. Thetopical formulations may desirably include a compound which enhancesabsorption or penetration of the active ingredient through the skin orother affected areas. Examples of such dermal penetration enhancersinclude dimethyl sulfoxide and related analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it desirably comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

Aqueous suspensions of Formula Ia or Ib compounds contain the activematerials in admixture with excipients suitable for the manufacture ofaqueous suspensions. Such excipients include a suspending agent, such assodium carboxymethylcellulose, croscarmellose, povidone,methylcellulose, hydroxypropyl methylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing orwetting agents such as a naturally occurring phosphatide (e.g.,lecithin), a condensation product of an alkylene oxide with a fatty acid(e.g., polyoxyethylene stearate), a condensation product of ethyleneoxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxybenzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

The pharmaceutical compositions of compounds of Formula Ia or Ib may bein the form of a sterile injectable preparation, such as a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, such as a solution in 1,3-butanediol or prepared as alyophilized powder. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile fixed oils may conventionally be employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid may likewise be used in the preparationof injectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, for exampleabout 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis disorders as described below.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

The formulations may be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefore. Veterinary carriers are materials useful for thepurpose of administering the composition and may be solid, liquid orgaseous materials which are otherwise inert or acceptable in theveterinary art and are compatible with the active ingredient. Theseveterinary compositions may be administered parenterally, orally or byany other desired route.

Combination Therapy

The compounds of Formulas Ia and Ib may be employed alone or incombination with other therapeutic agents for the treatment of a diseaseor disorder described herein, such as a hyperproliferative disorder(e.g., cancer). In certain embodiments, a compound of Formula Ia or Ibis combined in a pharmaceutical combination formulation, or dosingregimen as combination therapy, with a second compound that hasanti-hyperproliferative properties or that is useful for treating ahyperproliferative disorder (e.g., cancer). The second compound of thepharmaceutical combination formulation or dosing regimen preferably hascomplementary activities to the compound of Formula Ia or Ib such thatthey do not adversely affect each other. Such compounds are suitablypresent in combination in amounts that are effective for the purposeintended. In one embodiment, a composition of this invention comprises acompound of Formula Ia or Ib, or a stereoisomer, geometric isomer,tautomer, solvate, metabolite, or pharmaceutically acceptable salt orprodrug thereof, in combination with a chemotherapeutic agent such asdescribed herein.

The combination therapy may be administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations. The combinedadministration includes coadministration, using separate formulations ora single pharmaceutical formulation, and consecutive administration ineither order, wherein preferably there is a time period while both (orall) active agents simultaneously exert their biological activities.

Suitable dosages for any of the above coadministered agents are thosepresently used and may be lowered due to the combined action (synergy)of the newly identified agent and other chemotherapeutic agents ortreatments.

The combination therapy may provide “synergy” and prove “synergistic”,i.e., the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect may be attained when the compounds are administered or deliveredsequentially, e.g., by different injections in separate syringes. Ingeneral, during alternation therapy, an effective dosage of each activeingredient is administered sequentially, i.e., serially, whereas incombination therapy, effective dosages of two or more active ingredientsare administered together.

In a particular embodiment of anti-cancer therapy, a compound of FormulaIa or Ib, or a stereoisomer, geometric isomer, tautomer, solvate,metabolite, or pharmaceutically acceptable salt or prodrug thereof, maybe combined with other chemotherapeutic, hormonal or antibody agentssuch as those described herein, as well as combined with surgicaltherapy and radiotherapy. Combination therapies according to the presentinvention thus comprise the administration of at least one compound ofFormula Ia or Ib, or a stereoisomer, geometric isomer, tautomer,solvate, metabolite, or pharmaceutically acceptable salt or prodrugthereof, and the use of at least one other cancer treatment method. Theamounts of the compound(s) of Formula Ia or Ib and the otherpharmaceutically active chemotherapeutic agent(s) and the relativetimings of administration will be selected in order to achieve thedesired combined therapeutic effect.

Metabolites of Compounds of Formulas Ia and Ib

Also falling within the scope of this invention are the in vivometabolic products of Formulas Ia and Ib described herein. Such productsmay result for example from the oxidation, reduction, hydrolysis,amidation, deamidation, esterification, deesterification, enzymaticcleavage, and the like, of the administered compound. Accordingly, theinvention includes metabolites of compounds of Formulas Ia and Ib,including compounds produced by a process comprising contacting acompound of this invention with a mammal for a period of time sufficientto yield a metabolic product thereof.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Prodrugs of Formula Ia and Ib Compounds

In addition to compounds of Formulas Ia and Ib, the invention alsoincludes pharmaceutically acceptable prodrugs of such compounds.Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of a compound of the presentinvention. The amino acid residues include but are not limited to the 20naturally occurring amino acids commonly designated by three lettersymbols and also includes phosphoserine, phosphothreonine,phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine,gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylicacid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, citrulline, homocysteine, homoserine,methyl-alanine, para-benzoylphenylalanine, phenylglycine,propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of Formula Ia or Ib can be derivatized asan amide or alkyl ester. As another example, compounds of this inventioncomprising free hydroxy groups may be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Advanced DrugDelivery Reviews, (1996) 19:115. Carbamate prodrugs of hydroxy and aminogroups are also included, as are carbonate prodrugs, sulfonate estersand sulfate esters of hydroxy groups. Derivatization of hydroxy groupsas (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group maybe an alkyl ester optionally substituted with groups including, but notlimited to, ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem.,(1996), 39:10. More specific examples include replacement of thehydrogen atom of the alcohol group with a group such as(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and (X-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

Free amine groups of compounds of Formulas Ia and Ib can also bederivatized as amides, sulfonamides or phosphonamides. All of thesemoieties may incorporate groups including, but not limited to, ether,amine and carboxylic acid functionalities. For example, a prodrug can beformed by the replacement of a hydrogen atom in the amine group with agroup such as R-carbonyl, RO-carbonyl, NRR′-carbonyl, wherein R and R′are each independently (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, or benzyl, orR-carbonyl is a natural α-aminoacyl or natural α-aminoacyl-naturalα-aminoacyl, —C(OH)C(O)OY wherein Y is H, (C₁-C₆)alkyl or benzyl,—C(OY₀)Y₁ wherein Y₀ is (C₁-C₄) alkyl and Y₁ is (C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N—(C₁-C₆)alkylaminoalkyl, or —C(Y₂)Y₃ wherein Y₂ is H or methyl andY₃ is mono-N— or di-N,N—(C₁-C₆)alkylamino, morpholino, piperidin-1-yl orpyrrolidin-1-yl.

For additional examples of prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference.

Articles of Manufacture

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment of the diseases anddisorders described above is provided. In one embodiment, the kitcomprises a container comprising a compound of Formula Ia or Ib, or astereoisomer, geometric isomer, tautomer, solvate, metabolite, orpharmaceutically acceptable salt or prodrug thereof. The kit may furthercomprise a label or package insert on or associated with the container.The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts. Suitable containers include, for example, bottles, vials,syringes, blister pack, etc. The container may be formed from a varietyof materials such as glass or plastic. The container may hold a compoundof Formula Ia or Ib or a formulation thereof which is effective fortreating the condition and may have a sterile access port (for example,the container may be an intravenous solution bag or a vial having astopper pierceable by a hypodermic injection needle). At least oneactive agent in the composition is a compound of Formula Ia or Ib. Thelabel or package insert indicates that the composition is used fortreating the condition of choice, such as cancer. In addition, the labelor package insert may indicate that the patient to be treated is onehaving a disorder such as a hyperproliferative disorder,neurodegeneration, cardiac hypertrophy, pain, migraine or aneurotraumatic disease or event. In one embodiment, the label or packageinserts indicates that the composition comprising a compound of FormulaIa or Ib can be used to treat a disorder resulting from abnormal cellgrowth. The label or package insert may also indicate that thecomposition can be used to treat other disorders. Alternatively, oradditionally, the article of manufacture may further comprise a secondcontainer comprising a pharmaceutically acceptable buffer, such asbacteriostatic water for injection (BWFI), phosphate-buffered saline,Ringer's solution and dextrose solution. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, and syringes.

The kit may further comprise directions for the administration of thecompound of Formula Ia or Ib and, if present, the second pharmaceuticalformulation. For example, if the kit comprises a first compositioncomprising a compound of Formula Ia or Ib and a second pharmaceuticalformulation, the kit may further comprise directions for thesimultaneous, sequential or separate administration of the first andsecond pharmaceutical compositions to a patient in need thereof.

In another embodiment, the kits are suitable for the delivery of solidoral forms of a compound of Formula Ia or Ib, such as tablets orcapsules. Such a kit preferably includes a number of unit dosages. Suchkits can include a card having the dosages oriented in the order oftheir intended use. An example of such a kit is a “blister pack”.Blister packs are well known in the packaging industry and are widelyused for packaging pharmaceutical unit dosage forms. If desired, amemory aid can be provided, for example in the form of numbers, letters,or other markings or with a calendar insert, designating the days in thetreatment schedule in which the dosages can be administered.

According to one embodiment, a kit may comprise (a) a first containerwith a compound of Formula Ia or Ib contained therein; and optionally(b) a second container with a second pharmaceutical formulationcontained therein, wherein the second pharmaceutical formulationcomprises a second compound with anti-hyperproliferative activity.Alternatively, or additionally, the kit may further comprise a thirdcontainer comprising a pharmaceutically-acceptable buffer, such asbacteriostatic water for injection (BWFI), phosphate-buffered saline,Ringer's solution and dextrose solution. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, and syringes.

In certain other embodiments wherein the kit comprises a composition ofFormula Ia or Ib and a second therapeutic agent, the kit may comprise acontainer for containing the separate compositions such as a dividedbottle or a divided foil packet, however, the separate compositions mayalso be contained within a single, undivided container. Typically, thekit comprises directions for the administration of the separatecomponents. The kit form is particularly advantageous when the separatecomponents are preferably administered in different dosage forms (e.g.,oral and parenteral), are administered at different dosage intervals, orwhen titration of the individual components of the combination isdesired by the prescribing physician.

General Preparative Procedures

The Suzuki-type coupling reaction is useful to attach a fused bicyclicheterocycle or fused bicyclic heteroaryl at the 2-position of thepyrimidine ring (see Scheme 4). Generally, substituted2-chloro-4-morpholinothieno[3,2-d]pyrimidine 5 or2-chloro-4-morpholinothieno[2,3-d]pyrimidine 6 may be combined with 1.5equivalents of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7, anddissolved in 3 equivalents of sodium carbonate as a 1 molar solution inwater and an equal volume of acetonitrile. A catalytic amount, or more,of a low valent palladium reagent, such asbis(triphenylphosphine)palladium(II) dichloride, is added. A variety ofboronic acids or boronic esters can be used in place of the indazoleboronic ester indicated. Also alternatively, the nitrogen of theindazole may be protected, for example with a tetrahydropyranyl group;see compound 40. In some cases potassium acetate was used in place ofsodium carbonate to adjust the pH of the aqueous layer. The reaction wasthen heated to about 140-150° C. under pressure in a Biotage Optimizermicrowave reactor (Biotage, Inc.) for 10 to 30 minutes. The contents areextracted with ethyl acetate, or another organic solvent. Afterevaporation of the organic layer the product, 8 or 9, may be purified onsilica or by reverse phase HPLC.

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 or2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylicacid 14 is treated with 1.5 eq HATU, 3 eq of alkylamine and 3 eq ofDIPEA in DMF to approximately 0.1 M concentration. The reaction isstirred until complete and extracted in ethylacetate with saturatedbicarbonate solution one time. The organic layer is dried, filtered andconcentrated to yield the crude intermediate. This intermediate ispurified via reverse phase HPLC to yield product 15 or 16.

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonyl chloride 17 wassuspended in 1 mL of DCM before addition of 2 eq of amine and 3 eq ofDIPEA. The reactions were monitored by LCMS until complete. The crudereaction mixtures were diluted with ethyl acetate, extracted withsaturated ammonium chloride and back-extracted once with ethyl acetate.The organic layers were combined and concentrated to dryness. The crudesulfonamide intermediates 18 were used directly in the subsequent Suzukicouplings.

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine 4 was suspended to a 0.2molar concentration in THF and cooled to −50° C. in a dryice/acetonitrile bath before adding 2 equivalents of 2.5 M nBuLi inhexanes. After 15 min 3.0 molar equivalents of a cyclic or acyclicketone was added to the solution. The reaction continued to stir at −50°C. for 1 h and then in most cases was allowed to come to 0° C. When thereaction was complete by TLC or mass spec. it was quenched into asaturated ammonium chloride solution and extracted two times with EtOAc.The organic layer was concentrated and either used as a crude mixture,purified on silica, or the product 12 could be dissolved in a minimalamount of acetonitrile and filtered to remove remaining startingmaterial 4.

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (1 eq),phenylboronic acid or heterocycleboronic acid (R¹—B(OH)₂, 1.1 eq) andbis(triphenylphosphine)palladium(II) dichloride (0.1 eq) in 1 M Na₂CO₃aqueous solution (3 eq) and acetonitrile (3 eq) was heated to 100° C. ina sealed microwave reactor for 10 to 40 min to give 20. Upon completion,4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (1.3 eq)and bis(triphenylphosphine)palladium(II) dichloride (0.1 eq) were addedin the same pot. The reaction mixture was heated to 150° C. in a sealedmicrowave reactor for 10 to 15 min. The mixture was extracted with ethylacetate (3×5 mL). The combined organic layers were concentrated to yieldcrude 21.

2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine 22 (1 eq), Acidchloride (1.5˜2 eq) and triethylamine (2 eq) in dichloromethane wasstirred. The reaction was monitored by LC/MS until complete. The mixturewas evaporated to give the crude amide 23, which was directly used forthe next step reaction without purification.

To a 0.25 to 0.40 M solution of1-(2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)-N-methylmethanaminein DCM cooled to 0° C. was added 1.5 eq. of TEA, followed by thedrop-wise addition of 1.0 to 1.5 eq. of an alkyl or aryl-acid chlorideor sulfonylchloride, diluted in DCM. The reaction is stirred at ambienttemperature and monitored for completeness by LCMS. After completion,the reaction volume is increased with DCM, and dilute aqueous sodiumbicarbonate is added to the solution. The organic and aqueous layers areseparated. Finally, the organic layer is washed with brine and dried(MgSO₄). The dried organic solution is concentrated in vacuo andpurified by silica chromatography if desired

3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine 24 (1eq), carboxylic acid (RCO₂H, 1.5 eq), 1-hydroxy-7-azabenzotriazole (0.2eq), O-(7-azabenzotriazol-1-yl)-(N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 1.5 eq), and N,N-diisopropylethylamine (2.5eq) in DMF was stirred at room temperature. The reaction was monitoredby LC/MS until complete. The reaction mixture was diluted with ethylacetate, washed with saturated sodium bicarbonate and brine. The organiclayer was dried over MgSO₄, filtered and evaporated to yield amideproduct 25.

To a solution of 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19(0.05 g, 0.13 mmol) in DMF (1.00 ml) was added the appropriate aniline(200 mol %), Cs-₂CO₃ (50 mol %), Pd₂(dba)₃ (5 mol %), and XANTPHOS (10mol %). The reaction was heated to 110° C. under pressure in a Biotageoptimizer microwave reactor for 30 min. The resulting solution wasconcentrated in vacuo to give 26, after following General Procedure A.

To a solution of(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 (50 mg,0.2 mmol) in CH₂Cl₂ (4 mL) was added Et₃N (84 μL, 0.6 mmol) and theappropriate acid chloride or HCl salt thereof (0.3 mmol). The reactionstirred 18-48 hr at room temperature before being quenched with water.The aqueous layer was extracted with EtOAc. The combined organics weredried over Na₂SO₄ and concentrated in vacuo. The 2-chloro crude productwas coupled with boronate reagent 7 and palladium catalyst according toGeneral Procedure A to give 28 which was purified by reversed phase HPLCpurification.

Alternatively, to a solution of(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 (111mg, 0.39 mmol) in DMF (5 mL) was added 2,6-lutidine (48.2 μL, 0.41 mmol)and the appropriate acid chloride or HCl salt thereof (0.39 mmol). Thereaction stirred 18-72 hr at room temperature before being quenched withwater. The aqueous layer was extracted with EtOAc. The combined organicswere dried over MgSO₄ and concentrated in vacuo. The 2-chloro crudeproduct was coupled with boronate reagent 7 and palladium catalystaccording to General Procedure A to give 20 mg of 28 which was purifiedby reversed phase HPLC purification.

A mixture of2-chloro-6-(6-fluoropyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidine or2-chloro-6-(6-fluoropyridin-3-yl)-4-morpholinothieno[2,3-d]pyrimidinecompound, about four equivalents of a primary or secondary amine (R═H,C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl), and about two eq.diisopropylethylamine in N-methylpyrrolidine (˜0.1M) is heated to about130-140° C. in a sealed microwave reactor for 10˜40 min, followed byremoval of volatiles under high vacuum. The crude mixture is purified byflash chromatography to give intermediate2-chloro-6-(6-aminopyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidine or2-chloro-6-(6-aminopyridin-3-yl)-4-morpholinothieno[2,3-d]pyrimidinecompound, which may be Suzuki coupled with a fused bicyclic heterocycleor heteroaryl boronate reagent following General Procedure A.

EXAMPLES

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare a numberof other PI3K inhibitors of the invention, and alternative methods forpreparing the compounds of this invention are deemed to be within thescope of this invention. For example, the synthesis of non-exemplifiedcompounds according to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds of the invention.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, Lancaster,TCI or Maybridge, and were used without further purification unlessotherwise indicated.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was conducted on a Biotage system (Manufacturer:Dyax Corporation) having a silica gel column or on a silica SEP PAK®cartridge (Waters). ¹H NMR spectra were recorded on a Varian instrumentoperating at 400 MHz. ¹H NMR spectra were obtained in deuterated CDCl₃,d₆-DMSO, CH₃OD or d₆-acetone solutions (reported in ppm), usingchloroform as the reference standard (7.25 ppm). When peakmultiplicities are reported, the following abbreviations are used: s(singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd(doublet of doublets), dt (doublet of triplets). Coupling constants,when given, are reported in Hertz (Hz).

Example 1 2,4-Dichloro-thieno[3,2-d]pyrimidine 3

A mixture of methyl 3-amino-2-thiophenecarboxylate 1 (13.48 g, 85.85mmol) and urea (29.75 g, 5 eq.) was heated at 190° C. for 2 hours. Thehot reaction mixture was poured onto sodium hydroxide solution and anyinsoluble material was removed by filtration. The mixture was thenacidified (HCl, 2N) to yield 1H-thieno[3,2-d]pyrimidine-2,4-dione 2 as awhite precipitate, which was collected by filtration and air dried (9.49g, 66%). ¹H NMR 400 MHz, d₆-DMSO) 6.90 (1H, d, J=5.2 Hz), 8.10 (1H, d,J=5.2 Hz), 11.60-11.10 (2H, br s).

A mixture of 1H-thieno[3,2-d]pyrimidine-2,4-dione 2 (9.49 g, 56.49 mmol)and phosphorous oxychloride (150 mL) was heated at reflux for 6 h. Thereaction mixture was then cooled and poured onto ice/water with vigorousstirring yielding a precipitate. The mixture was then filtered to yield2,4-dichloro-thieno[3,2-d]pyrimidine 3 as a white solid (8.68 g, 75%).¹H NMR (400 MHz, CDCl₃) 7.56 (1H, d, J=5.5 Hz), 8.13 (1H, d, J=5.5 Hz).

Example 2 2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4

A mixture of 2,4-dichloro-thieno[3,2-d]pyrimidine 3, (8.68 g, 42.34mmol), morpholine (8.11 mL, 2.2 eq.) and MeOH (150 mL) was stirred atroom temperature for 1 h. The reaction mixture was then filtered, washedwith water and MeOH, to yield2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 as a white solid(11.04 g, 100%). ¹H NMR (400 MHz, d₆-DMSO) 3.74 (4H, t, J=4.9 Hz), 3.90(4H, t, J=4.9 Hz), 7.40 (1H, d, J=5.6 Hz), 8.30 (1H, d, J=5.6 Hz).

Example 32-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10

To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4(1.75 g, 6.85 mmol) in dry THF (40 mL) at −78° C. was added a 2.5Msolution of n-butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.). Afterstirring for 1 h, dry DMF (796 μL, 1.5 eq.) was added. The reactionmixture was stirred for 1 h at −78° C. and then warmed slowly to roomtemperature. After a further 2 h at room temperature the reactionmixture poured onto ice/water yielding a yellow precipitate. This wascollected by filtration and air-dried to yield2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10(1.50 g, 77%). ¹H NMR (400 MHz, d₆-DMSO) 3.76 (4H, t, J=4.9), 3.95 (4H,t, J=4.9), 8.28 (1H, s), 10.20 (1H, s).

Also, to a suspension of4-(2-chlorothieno[2,3-d]pyrimidin-4-yl)morpholine (1.75 g, 6.85 mmol) indry THF at −78° C. was added a 2.5M solution of n-butyllithium (nBuLi)in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 uL,1.5 eq.) was added. The reaction mixture was stirred for 1 h at −78° C.and then warmed slowly to room temperature. After a further 2 h at roomtemperature the reaction mixture was poured onto ice/water yielding ayellow precipitate. This was collected by filtration and air-dried toyield 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (1.5g, 77% yield) MS (Q1) 284 (M)+

Example 4 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole7-route 1

To a solution of 3-bromo-2-methyl aniline (5.0 g, 26.9 mmol) inchloroform (50 mL) was added potassium acetate (1.05 eq., 28.2 mmol,2.77 g). Acetic anhydride (2.0 eq., 53.7 mmol, 5.07 mL) was added withconcurrent cooling in ice-water. The mixture was then stirred at roomtemperature for 10 minutes after which time a white gelatinous solidformed. 18-Crown-6 (0.2 eq., 5.37 mmol, 1.42 g) was then added followedby iso-amyl nitrite (2.2 eq., 59.1 mmol, 7.94 mL) and the mixture washeated under reflux for 18 h. The reaction mixture was allowed to cool,and was partitioned between chloroform (3×100 mL) and saturated aqueoussodium hydrogen carbonate (100 mL). The combined organic extracts werewashed with brine (100 mL), separated and dried (MgSO₄).

The crude product was evaporated onto silica and purified bychromatography eluting with 20%→40% EtOAc-petrol to give1-(4-bromo-indazol-1-yl)-ethanone A (3.14 g, 49%) as an orange solid,and 4-bromo-1H-indazole B (2.13 g, 40%) as a pale orange solid.

A ¹H NMR (400 MHz, CDCl₃) 2.80 (3H, s), 7.41 (1H, t, J=7.8 Hz), 7.50(1H, d, J=7.8 Hz), 8.15 (1H, s), 8.40 (1H, d, J=7.8 Hz).

B: ¹H NMR (400 MHz, CDCl₃) 7.25 (1H, t, J=7.3 Hz), 7.33 (1H, d, J=7.3Hz), 7.46 (1H, d, J=7.3 Hz), 8.11 (1H, s), 10.20 (1H, br s).

To a solution of the 1-(4-bromo-indazol-1-yl)-ethanone A (3.09 g, 12.9mmol) in MeOH (50 mL) was added 6N aqueous HCl (30 mL) and the mixturewas stirred at room temperature for 7 h. The MeOH was evaporated and themixture partitioned between EtOAc (2×50 mL) and water (50 mL). Thecombined organic layers were washed with brine (50 mL), separated anddried (MgSO₄). The solvent was removed by evaporation under reducedpressure to give 4-bromo-1H-indazole B (2.36 g, 93%).

To a solution of the 4-bromo-1H-indazole B (500 mg, 2.54 mmol) andbis(pinacolato)diboron (1.5 eq., 3.81 mmol) in DMSO (20 mL) was addedpotassium acetate (3.0 eq., 7.61 mmol, 747 mg; dried in drying pistol)and PdCl₂(dppf)₂ (3 mol %, 0.076 mmol, 62 mg). The mixture was degassedwith argon and heated at 80° C. for 40 h. The reaction mixture wasallowed to cool and partitioned between water (50 mL) and ether (3×50mL). The combined organic layers were washed with brine (50 mL),separated and dried (MgSO₄). The crude material was purified bychromatography eluting with 30%→40% EtOAc-petrol to give an inseparable3:1 mixture of the4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole 7 (369 mg,60%) and indazole (60 mg, 20%), isolated as a yellow gum whichsolidified upon standing to furnish as an off-white solid. ¹H NMR (400MHz, d₆-DMSO) 1.41 (12H, s), 7.40 (1H, dd, J=8.4 Hz, 6.9 Hz), 7.59 (1H,d, J=8.4 Hz), 7.67 (1H, d, J=6.9 Hz), 10.00 (1H, br s), 8.45 (1H, s),and indazole: 7.40 (1H, t), 7.18 (1H, t, J=7.9 Hz), 7.50 (1H, d, J=9.1Hz), 7.77 (1H, d, J=7.9 Hz), 8.09 (1H, s). Impurity at 1.25.

Example 5 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole7-route 2

To a solution of 2-methyl-3-nitroaniline (2.27 g, 14.91 mmol) in aceticacid (60 mL) was added a solution of sodium nitrite (1.13 g, 1.1 eq.) inwater (5 mL). After 2 h, the deep red solution was poured onto ice/waterand the resulting precipitate collected by filtration to yield4-nitro-1H-indazole C (1.98 g, 81%).

A mixture of 4-nitro-1H-indazole C (760 mg, 4.68 mmol), palladium oncharcoal (10%, cat.) and ethanol (30 mL) was stirred under a balloon ofhydrogen for 4 h. The reaction mixture was then filtered through celite,and the solvent removed in vacuo to yield 1H-indazol-4-ylamine D (631mg, 100%).

An aqueous solution of sodium nitrite (337 mg, 4.89 mmol) in water (2mL) was added dropwise to a suspension of 1H-indazol-4-ylamine D (631mg, 4.74 mmol) in 6M hydrochloric acid (7.2 mL) at below 0° C. Afterstirring for 30 minutes, sodium tetrafluoroborate (724 mg) was added tothe reaction mixture. A viscous solution resulted, which was filteredand washed briefly with water to yield 1H-indazole-4-diazoniumtetrafluoroborate salt E (69) (218 mg, 20%) as a deep red solid.

Dry methanol (4 mL) was purged with argon for 5 minutes. To this wasadded 1H-indazole-4-diazonium tetrafluoroborate salt (218 mg, 0.94mmol), bis-pinacolato diboron (239 mg, 1.0 eq.) and[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride (20 mg).The reaction mixture was stirred for 5 h and then filtered throughcelite. The residue was purified using flash chromatography to yield4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole 7, (117mg).

Example 6 6-Fluoroindazole-4-Boronate Ester 7a

To a solution of 4-fluoro-2-nitrotoluene (3.44 g) in trifluoroaceticacid (13 mL) was added concentrated sulfuric acid (4 mL) followed byN-bromosuccinimide (5.92 g). The reaction mixture was stirred for 16 hand was then quenched with brine, extracted into ethyl acetate, anddried (MgSO₄). The solvent was removed in vacuo to furnish crude1-bromo-5-fluoro-2-methyl-3-nitro-benzene (5.96 g).

To a solution of crude 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (5.96g) in MeOH (90 mL) was added concentrated hydrochloric acid (11.7 mL)and iron (6.1 g) and the reaction mixture was heated to reflux. After 16h, the mixture was cooled, diluted with DCM, washed with sodiumcarbonate solution, dried (MgSO₄) and the solvent removed in vacuo. Theresidue was purified using flash chromatography to yield3-bromo-5-fluoro-2-methyl-phenylamine (1.46 g).

To a solution of 3-bromo-5-fluoro-2-methyl-phenylamine (470 mg) indioxane (6 mL) was added triethylamine (1.28 mL), palladium acetate (25mg), 2-dicyclohexylphosphino biphenyl (161 mg) and pinacol borane (1.001ml) and the mixture was heated to 80° C. for 4 h. The reaction mixturewas cooled, diluted with chloroform, washed with brine, dried (MgSO₄)and the solvent removed in vacuo. The residue was purified using flashchromatography to yield 7a (466 mg).

Example 6a6-(Tributylstannyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine50

To 3.07 g of 5-bromo-2,3-diaminopyridine was added 20 mL formic acidunder N₂ and the reaction was heated to reflux for four hours andallowed to cool to room temperature. The reaction was stirred overnightat room temperature and complete reaction was confirmed by LCMS. Thesolution was concentrated in vacuo and purified by flash chromatography(DCM/MeOH) to give 1.64 g of compound 47 (51% yield). Compound 47 (1.64g) in 40 mL THF was added to 0.22 g (1.1 eq) NaH in 10 mL THF under N₂at −78° C. The reaction was stirred at −78° C. for 30 minutes followedby the addition of 1.45 g of SEM-Cl (1.05 eq) and allowed to warm up toroom temperature. The reaction was stirred at room temperature overnightand complete reaction was confirmed by LCMS. The reaction was quenchedwith water followed by the addition of NaCl (not saturated) and the twoproducts extracted with EtOAc and concentrated in vacuo. The tworegioisomers were separated by flash chromatography (EtOAc/Hexanes) togive 1.68 g 48 and 0.5 g 49 (80% overall yield). Compound 49 (0.5 g) wasdissolved in 50 mL dioxane followed by the addition of 1.76 g (2.0 eq)of Bis (tributyltin), 88 mg (0.05 eq) of Pd(PPh₃)₄, and 0.19 g (3.0 eq)of LiCl. The reaction mixture was heated to reflux under N₂ for 1.5hours and complete reaction confirmed by LCMS. The mixture was cooled toroom temperature, filtered through celite (celite washed with EtOAc),rotovapped and purified by flash chromatography (EtOAc/Hexanes) to give501 mg of6-(tributylstannyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine50 (61% yield). MS (Q1) 539.2 (M)+

Example 6b2-Methyl-6-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine54

To 5.06 g of 5-bromo-2,3-diaminopyridine was added 50 mL acetic acidunder N₂ and the reaction was heated to reflux overnight. Completereaction was confirmed by LCMS. The solution was concentrated in vacuoand purified by flash chromatography (DCM/MeOH) to give 4.68 g ofcompound 51 (82% yield). Compound 51 (4.68 g) in 150 mL THF was added to0.63 g (1.1 eq) NaH in 10 mL THF under N₂ at −78° C. The reaction wasstirred at −78° C. for 30 minutes followed by the addition of 3.86 g ofSEM-Cl (1.05 eq) and allowed to warm up to room temperature. Thereaction was stirred at room temperature 4.5 hours and complete reactionwas confirmed by LCMS. The reaction was quenched with water followed bythe addition of NaCl (not saturated) and the two products extracted withEtOAc and concentrated in vacuo. The two regioisomers were separated byflash chromatography (EtOAc/Hexanes) to give 2.84 g 52 and 1.94 g 53(63% overall yield). Compound 52 (2.08 g) was dissolved in 50 mL toluenefollowed by the addition of 2.32 g (1.5 eq) of Bis (pinacolato)diboron,0.24 g (0.05 eq) of PdCl₂(dppf), and 1.79 g (3.0 eq) of KOAc. Thereaction mixture was heated to 95° C. under N₂ and let stir overnight.Complete reaction confirmed by LCMS. The mixture was cooled to roomtemperature, rotovapped and purified by flash chromatography(EtOAc/Hexanes) to give 1.83 g of2-methyl-6-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine54 (77% yield). MS (Q1) 390.2 (M)+

Example 72-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde11

A mixture of2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (100mg, 0.35 mmol),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (70) (95mg, 0.39 mmol) and sodium carbonate (112 mg) were suspended in toluene(2.5 mL), ethanol (1.5 mL) and water (0.7 mL). To this was addedbis(triphenylphosphine)palladium(II) chloride (13.5 mg) and the reactionvessel was flushed with argon. The reaction mixture was microwaved at120° C. for 1 h and then partitioned between DCM and water, the organiclayer was washed with brine, dried over magnesium sulfate, filtered andevaporated in vacuo. The resulting residue was purified using flashchromatography to yield2-(1H-indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde11 (97 mg).

Example 8 (2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanol 29

A solution of2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 10 (1.0 g,3.5 mmol) in MeOH (30 mL) at 0° C. was treated with NaBH₄ (0.1 g, 3.5mmol). The solution was allowed to warm to room temperature and stirred15 min. The reaction mixture was quenched with a mixture of a saturatedsolution of sodium bicarbonate and water (1:1, v/v). The aqueoussolution was extracted with EtOAc. The combined organic layers weredried over Na₂SO₄ and concentrated in vacuo. The crude material 29required no further purification (0.9 g, 90%). MS (Q1) 286 (M)+

Example 9 6-(Bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine30

To a solution of(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanol 29 (100 mg,0.4 mmol) in benzene (3.0 mL) at 0° C. was added PBr₃ (30 μL, 0.4 mmol).The reaction was heated at reflux for 1 hour. After cooling to roomtemperature the reaction was quenched by the addition of water. Theaqueous layer was extracted with EtOAc. The combined organics were driedover Na₂SO₄ and concentrated in vacuo. The crude product 30 did notrequire further purification (115 mg, 94%). MS (Q1) 350 (M)+

Example 102-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)isoindoline-1,3-dione31

To a solution of6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 (0.3 g,0.9 mmol) in DMF (10 mL) was added K₂CO₃ (0.2 g, 1.3 mmol), andphthalimide (0.1 g, 0.9 mmol). The resulting solution stirred 20 h atroom temperature. The reaction was concentrated in vacuo and dilutedwith water (10 mL). The heterogeneous mixture was filtered to afford2-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)isoindoline-1,3-dione31 (0.3 g, 75%). MS (Q1) 415 (M)+

Example 11 (2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine27

To a solution of2-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)isoindoline-1,3-dione31 (100 mg, 0.24 mmol) in MeOH (7 mL) was added H₂NNH₂.H₂O (24 μL, 0.48mmol). The reaction was heated at reflux for 1 h. After cooling to roomtemperature the reaction was quenched with water (10 mL) and extractedwith EtOAc. The combined organics were dried over Na₂SO₄ andconcentrated in vacuo to afford(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 (0.05g, 73%). MS (Q1) 285 (M)+

Example 11a1(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine55

To 3.0 g of2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 in50 mL Toluene and 50 mL THF was added 30 mL of NH₂ME (40% in water) andthe mixture stirred under N₂ for two days. The mixture was concentratedin vacuo and redissolved in 50 mL THF and 50 mL MeOH followed by theportionwise addition of 1.6 g (4.0 eq) NaBH₄ and the reaction mixturestirred overnight at room temperature. Complete reaction was confirmedby LCMS and the mixture was concentrated in vacuo and purified by flashchromatography (95/5% EtOAc/EtOH 20 min followed by a gradient up to100% EtOH over 30 min more) to give 2.45 g of1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine55 (77.5% yield). MS (Q1) 300 (M)+

Also, to a solution of2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (2.0 g)in 50 mL THF was added 20 mL of 40% methylamine in water. The reactionmixture was stirred at room temperature under N₂ for 24 hours. Thesolvents were removed in vacuo and the residue was dissolved in 50 mLMeOH and 50 mL THF and the NaBH₄ added portion-wise. This reactionmixture was stirred at room temperature under N₂ for 24 hours andcomplete reaction was confirmed by LCMS. The solvents were removed invacuo and the crude product purified by flash chromatography(EtOAc/EtOH) to give 1.12 g of1-(2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)-N-methylmethanamine(53% yield). MS (Q1) 300 (M)+

Example 11b1-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine56

To 3.46 g of2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde in20 mL toluene and 20 mL THF followed by the addition of 15 mL of NH₂ME(40% in water) and the mixture stirred under N₂ overnight. The mixturewas concentrated in vacuo and redissolved in 30 mL MeOH and 20 mL THFfollowed by the portionwise addition of 1.76 g (4.0 eq) NaBH₄ and thereaction mixture stirred four days at room temperature. Completereaction was confirmed by LCMS and the mixture was concentrated in vacuoand purified by flash chromatography (97/3% EtOAc/EtOH 20 min followedby a gradient up to 100% EtOH over 30 min more) to give 2.53 g of1-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine56 (70% yield). MS (Q1) 313.8 (M)+

Example 12 2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19

Following the procedures in U.S. Pat. No. 6,492,383, 2.5 M ofn-butylithium (9.4 mL, 22.48 mmol) in hexane solution was added to amixture of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (3.0 g, 11.74mmol) in 60 mL of THF at −78° C. The reaction mixture was allowed towarm to −40° C. and stirred for 30 min. A solution of iodine (6.0 g,23.48 mmol) in 10 mL of THF was added dropwise. After the addition wascompleted. The reaction mixture was brought to room temperature andstirred for 2 h. The mixture was quenched by diluting withdichloromethane and extracting with H₂O (2×100 mL). The organic layerwas washed with Na₂S₂O₃ (2×100 mL), H₂O (2×100 mL), dried over MgSO₄,filtered and evaporated to afford2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (3.4 g, 75%).

Also, to a solution of2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine (3.0 g, 11.1 mmol;prepared according to the procedure for the synthesis of2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine but commencing with3-amino-4-methyl-thiophene-2-carboxylic acid ethyl ester) in THF (60 mL)at −78° C. was added n-BuLi (8.9 mL, 2.5 M in Et₂O). The resultingslurry was warmed to −40° C. and stirred 50 min. The reaction mixturewas then cooled to −78° C. and a solution of I₂ (5.6 g, 22.2 mmol) inTHF (30 mL) was added. The solution was warmed to room temperature andstirred 5 h. The reaction was quenched by the addition of water. Theorganic layer was separated and the aqueous layer was extracted withCH₂Cl₂. The combined organics were washed with saturated aqueousNa₂S₂O₃, dried over Na₂SO₄, filtered, and concentrated in vacuo toprovide 2-chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine(3.8 g, 84% yield).

Example 13 Tert-butyl furan-3-ylcarbamate 32

3-Furoic acid (5.60 g, 1.0 eq) was dissolved in tert-butanol (200 ml)and treated with triethylamine (10 ml, 1.4 eq) and diphenyl phosphorylazide (12 ml, 1.1 eq). Mixture was heated at reflux for 18 h. Reactionmixture was cooled to room temperature, then concentrated to 50 ml andpoured into saturated aq. NaHCO₃. Mixture was stirred at 0° C. for 2 h.Solid was collected by filtration and dried under high vacuum. The crudereaction mixture was purified by flash chromatography to yieldtert-butyl furan-3-ylcarbamate 32 (6.95 g, 76%): ¹H NMR (CDCl₃, 400 MHz)δ 7.71 (bs, 1H), 7.27 (m, 1H), 6.27 (bs, 1H), 6.20 (bs, 1H), 1.50 (s,9H); MS (Q1) 184 (M)⁺.

Example 14 Tert-butyl 2-(methoxycarbonyl)furan-3-ylcarbamate 33

To a solution of tert-butyl furan-3-ylcarbamate 32 (1.7 g, 1.0 eq) inTHF (50 ml) at −30° C. was added TMEDA (1.75 ml, 1.3 eq) followed by1.6M solution of n-butyllithium (8.4 ml, 2.25 eq, 1.6M in hexanes).Reaction mixture was allowed to warm up to 0° C. and stirred for 1 h,before being cooled back to −30° C. Dimethyl carbonate (2.4 ml, 3.0 eq)was quickly added, before the reaction mixture was allowed to warm up toroom temperature for 1 hr. Reaction mixture was quenched with 2M HCl,followed by addition of saturated aq. NaCl. Mixture was extracted withethyl acetate. The combined organic extracts were dried with Na₂SO₄ andconcentrated. The crude reaction mixture was purified by flashchromatography to yield tert-butyl2-(methoxycarbonyl)furan-3-ylcarbamate 33 (1.14 g, 51%): MS (Q1) 242(M)⁺.

Example 15 Methyl 3-aminofuran-2-carboxylate 34

Tert-butyl 2-(methoxycarbonyl)furan-3-ylcarbamate 33 (1.14 g, 1.0 eq)was dissolved in dichloromethane (8 ml) and treated with trifluoroaceticacid (5 ml). Reaction mixture was stirred at room temperature for 3 h,and was then concentrated. Residue was dissolved in dichloromethane andwashed with saturated aq. NaHCO₃. The organic layer was dried (Na₂SO₄)and concentrated Mixture was extracted with ethyl acetate. The combinedorganic extracts were dried with Na₂SO₄ and concentrated. The crudereaction mixture was purified by flash chromatography to yield methyl3-aminofuran-2-carboxylate 34 (574 mg, 86%): MS (Q1) 142 (M)⁺.

Example 16 Ethyl 3-ureidofuran-2-carboxylate 35

To a solution of methyl 3-aminofuran-2-carboxylate 34 (100 mg, 1.0 eq)in dichloromethane (3 ml) at −78° C. was added chlorosulfonyl isocyanate(0.09 ml, 1.4 eq) dropwise. The reaction was slowly warmed to roomtemperature and stirred for 40 minutes. Reaction was concentrated. Tothe residue was added 6N HCl (3.5 ml) and mixture was heated to 100° C.for 20 minutes. Reaction mixture was allowed to cool down to roomtemperature, and was neutralized with saturated aq. NaHCO₃. Solid wascollected by filtration to yield ethyl 3-ureidofuran-2-carboxylate 35(120 mg, 92%) as a beige solid which was used in the next reactionwithout further purification.

Example 17 Furo[3,2-d]pyrimidine-2,4-diol 36

Ethyl 3-ureidofuran-2-carboxylate 35 (120 mg, 1.0 eq) was suspended inmethanol (6 ml) and treated with 1.5 M NaOH (1.5 ml). Reaction mixturewas heated to reflux for 90 minutes. Reaction mixture was allowed tocool down to room temperature, and was acidified with 6N HCl up to pH 3.Mixture was concentrated. Methanol was added to residue and solid wasfiltered and dried at 95° C. under high vacuum for 24 h to yieldfuro[3,2-d]pyrimidine-2,4-diol 36 (90 mg, 91%) which was used in thenext reaction without further purification.

Example 18 2,4-Dichlorofuro[3,2-d]pyrimidine 37

Furo[3,2-d]pyrimidine-2,4-diol 36 (39 mg, 1.0 eq) was dissolved in POCl₃(1.8 ml). Mixture was cooled to −40° C. and N,N-diisopropylethylamine(0.45 ml) wad slowly added. Reaction mixture was then heated to refluxfor 48 h, then cooled to room temperature Reaction mixture was pouredinto ice/water. Mixture was extracted with ethyl acetate. The combinedorganic layers were washed with saturated aq. NaHCO₃, dried (Na₂SO₄) andconcentrated to yield 2,4-dichlorofuro[3,2-d]pyrimidine 37 (23 mg, 48%)which was used in the next reaction without further purification.

Example 19 2-Chloro-4-morpholinofuro[3,2-d]pyrimidine 38

2,4-Dichlorofuro[3,2-d]pyrimidine 37 (23 mg, 1.0 eq) was suspended inmethanol (1.7 ml) and treated with morpholine (0.09 ml, 4.0 eq).Reaction mixture was stirred at room temperature for 2 h, before beingquenched with saturated aq. NaHCO₃. Mixture was extracted withdichloromethane. The combined organic layers were dried (Na₂SO₄) andconcentrated to yield 2-chloro-4-morpholinofuro[3,2-d]pyrimidine 38 (14mg, 48%) which was used in the next reaction without furtherpurification.

Example 20 2-Chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carbaldehyde 39

To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine 38 (40 mg,1.0 eq) dissolved in THF (1.7 ml) at −78° C. was added 1.6M solution ofn-butyllithium (0.14 ml, 1.3 eq, 1.6M in hexanes). Reaction mixture wasstirred at −78° C. for 30 minutes. DMF (0.05 ml, 4.0 eq) was added andreaction mixture was allowed to slowly warm up to room temperature andstirred for 90 minutes. Reaction mixture was quenched with water, andextracted with dichloromethane. The combined organic layers were dried(Na₂SO₄) and concentrated. The crude reaction mixture was purified byflash chromatography to yield2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carbaldehyde 39 (22 mg,50%): ¹H NMR (CDCl₃, 400 MHz) δ 9.92 (s, 1H), 7.48 (s, 1H), 4.12 (m,4H), 3.86 (dd, 4H); MS (Q1) 268 (M)⁺.

Example 211-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole40 Route A

Step A: Preparation of 4-chloro-1H-indazole: To a 250 ml flask withstirbar was added 2-methyl-3-chloroaniline (8.4 ml, 9.95 g, 70.6 mmol),potassium acetate (8.3 g, 84.7 mmol) and chloroform (120 ml). Thismixture was cooled to 0° C. with stirring. To the cooled mixture wasadded acetic anhydride (20.0 ml, 212 mmol) drop wise over 2 minutes. Thereaction mixture was warmed to 25° C. and stirred for 1 hour. At thispoint, the reaction was heated to 60° C. Isoamyl nitrite (18.9 ml, 141mmol) was added and the reaction was stirred overnight at 60° C. Oncecomplete, water (75 ml) and THF (150 ml) were added and the reaction wascooled to 0° C. LiOH (20.7 g, 494 mmol) was added and the reaction wasstirred at 0° C. for 3 hours. Water (200 ml) was added and the productwas extracted with EtOAc (300 ml, 100 ml). The organic layers werecombined, dried with MgSO₄ and concentrated in vacuo to yield 11.07 g(100%) as an orange solid. ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=1 Hz,1H), 7.33 (d, J=8 Hz 1H), 7.31 (t, J=7 Hz, 1H), 7.17 (dd, J=7 Hz, 1 Hz1H). LCMS (ESI pos) m/e 153 (M+1).

Step B: Preparation of4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole: To a 1 L flask withmechanical stirrer was added 4-chloro-1H-indazole (75.0 g, 0.492 mol),pyridinium p-toluenesulfonate (1.24 g, 4.92 mmol), CH₂Cl₂ (500 ml) and3,4-dihydro-2H-pyran (98.6 ml, 1.08 mol). With stirring, this mixturewas heated to 45° C. for 16 hours. Analysis of reaction mixture showsproduction of both isomers of product. Cooled reaction to 25° C. andadded CH₂Cl₂ (200 ml). Washed the solution with water (300 ml) andsaturated NaHCO₃ (250 ml). Dried the organics with MgSO₄ andconcentrated to dryness. Purified the crude product by dissolving inEtOAc/Hexanes (4:6, 1 L) and adding SiO₂ (1.2 L). The mixture wasfiltered and the cake was washed with EtOAc/Hexanes (4:6, 2 L). Theorganics were concentrated in vacuo to yield 110.2 g (95%) as an orangesolid. Isomer 1: ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=1 Hz, 1H), 7.50(dd, J=9 Hz, 1 Hz 1H), 7.29 (dd, J=9 Hz, 8 Hz 1H), 7.15 (dd, J=8 Hz, 1Hz 1H) 5.71 (dd, J=9 Hz, 3 Hz 1H) 4.02 (m, 1H) 3.55 (m, 1H) 2.51 (m, 1H)2.02 (m, 2H) 1.55 (m, 3H). LCMS (ESI pos) m/e 237 (M+1); Isomer 2: ¹HNMR (400 MHz, CDCl₃) δ 8.25 (d, J=1 Hz, 1H), 7.62 (dd, J=9 Hz, 1 Hz 1H),7.20 (dd, J=9 Hz, 8 Hz 1H), 7.06 (dd, J=8 Hz, 1 Hz 1H) 5.69 (dd, J=9 Hz,3 Hz 1H) 4.15 (m, 1H) 3.80 (m, 1H) 2.22 (m, 2H) 2.05 (m, 1H) 1.75 (m,3H). LCMS (ESI pos) m/e 237 (M+1).

Step C: Preparation of1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole:To a 500 ml flask with stirbar was added4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10.0 g, 42.2 mmol),DMSO (176 ml), PdCl₂(PPh₃)₂ (6.2 g, 8.86 mmol), tricyclohexylphosphine(0.47 g, 1.69 mmol), bis(pinacolato)diboron (16.1 g, 63.4 mmol) andpotassium acetate (12.4 g, 0.127 mol). With stirring, the mixture washeated to 130° C. for 16 hours. The reaction was cooled to 25° C. andEtOAc (600 ml) was added and washed with water (2×250 ml). The organicswere dried with MgSO₄ and concentrated in vacuo to dryness. The crudeproduct was purified by SiO₂ plug (120 g), eluting with 10%EtOAc/Hexanes (IL) and 30% EtOAc/Hexanes (1 L). The filtrate wasconcentrated in vacuo to give 13.9 g (100%) of product 40 as a 20%(wt/wt) solution in ethyl acetate. ¹H NMR shows the presence of ˜20%(wt/wt) bis(pinacolato)diboron. ¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1H),7.62 (dd, J=14 Hz, 2 Hz 1H), 7.60 (dd, J=7 Hz, 1 Hz 1H), 7.31 (dd, J=8Hz, 7 Hz 1H) 5.65 (dd, J=9 Hz, 3 Hz 1H) 4.05 (m, 1H) 3.75 (m, 1H) 2.59(m, 1H) 2.15 (m, 1H) 2.05 (m, 1H) 1.75 (m, 3H) 1.34 (s, 12H). LCMS (ESIpos) m/e 245 (M+1).

Example 22 1-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-indazole 40 Route B

Step A: Preparation of 4-nitro-1H-indazole: A mixture of2-methyl-3-nitro aniline (200 g, 1.315 moles), acetic acid (8000 ml) wascooled to 15-20° C. and a solution of sodium nitrite (90.6 g, 1.315moles) in water (200 ml) was slowly added over 30 min. After theaddition, the reaction temp. was increased to 25-30° C. and the reactionwas stirred at this temp for 2-3 h. Reaction progress was monitored byTLC and after completion of reaction product was filtered and residuewas washed with acetic acid (1000 ml). Acetic acid was distilled undervacuum (550 mm of Hg) below 80° C. and water (8000 ml) was added, cooledto 25-30° C. and stirred for 30 min. The slurry was filtered and washedwith water (1000 ml). Crude product was dried under heating at 70-80° C.for 2 hours, then was taken in 5% ethyl acetate/n-hexane (100:2000 ml)solution and stirred for 1-1.5 h at ambient temperature. The suspensionwas filtered and washed with 5% ethyl acetate/n-hexane mixture (25:475ml). The product obtained was dried under vacuum at below 80° C. for10-12 h to give a brown solid (150 g, 70%): m.p: 200-203° C.; ¹H NMR(200 MHz, CDCl₃) δ 13.4 (br, 1H), 8.6 (s, 1H), 8.2-7.95 (dd, 2H), 7.4(m, 1H). ESMS m/z 164 (M+1). Purity: 95% (HPLC)

Step B: Preparation of 4-amino-1H-indazole: A mixture of4-nitro-1H-indazole (200 g, 1.22 moles) and 10% palladium on carbon(20.0 g,) in EtOH (3000 ml) was hydrogenated at ambient temperature(reaction was exothermic and temperature increased to 50° C.). Aftercompletion of reaction, the catalyst was removed by filtration. Thesolvent was evaporated under vacuum at below 80° C. and cooled to roomtemperature and n-hexane (1000 ml) was added to the residue and stirredfor 30 min. Isolated solid was filtered and washed with n-hexane (200ml). Product was dried under vacuum at 70-80° C. for 10-12 h to give abrown solid (114 g, 70%), m.p.: 136-143° C. ¹H NMR (200 MHz, CDCl₃) δ 12(br, 1H), 8.0 (s, 1H), 7.1-7.0 (dd, 2H), 6.5 (d, 1H), 3.9 (m, 2H). ESMSm/z 134 (M+1). Purity: 90-95% (HPLC)

Step C: Preparation of 4-iodo-1H-indazole: A mixture of4-amino-1H-indazole (50.0 g, 0.375 moles) in water (100 ml) and con.hydrochloric acid (182 ml) was cooled to −10° C. To this a solution ofsodium nitrite (51.7 g, 0.75 moles) in water (75 ml) was added drop wiseat −10° C. in about 30-60 min. (during addition frothing was observed).In another flask a mixture of potassium iodide (311 g, 1.87 moles) inwater (3000 ml) was prepared at room temperature and to this abovecooled diazonium salt at 30-40° C. was added in about 30-40 min. Thereaction was maintained at 30° C. for 1 h and after completion ofreaction, ethyl acetate (500 ml) was added and the reaction mixture wasfiltered through Celite. The layers were separated and the aq. layer wasextracted with ethyl acetate (2×500 ml). The combined organic layerswere washed with 5% hypo solution (2×500 ml), brine (500 ml), dried(Na₂SO₄) and concentrated. Crude product was purified by chromatography(silica gel, hexane, 15-20% ethyl acetate/hexane) to furnish product asan orange solid (23.0 g, 25%). m.p: 151-177 C: ¹H NMR (200 MHz, CDCl₃) δ12.4 (br, 1H), 8.0 (s, 1H), 7.6 (dd, 2H), 7.1 (d, 1H). ESMS m/z 245(M+1). Purity: 95-98% (HPLC).

Step D: Preparation of 4-iodo-1-(2-tetrahydropyranyl) indazole: Amixture of 4-amino-1H-indazole (250.0 g, 1.024 moles),3,4-dihydro-2H-pyran (126.0 g, 1.5 moles) and PPTS (2.57 g, 0.01 moles)in CH₂Cl₂ (1250 ml) was heated to 50° C. for 2 h. The reaction wascooled to r.t and poured into water (625 ml), the layers were separated,and aqueous layer was extracted with CH₂Cl₂ (250 ml). The combinedorganic layers were washed with water (625 ml), dried (Na₂SO₄) andconcentrated. Crude residue was purified by chromatography (silica gel,hexane, 5-10% ethyl acetate/hexane) to furnish product as oil (807.0 g,60%). ¹H NMR (200 MHz, CDCl₃) δ 8.5 (s, 1H), 7.8 (m, 1H), 7.6 (d, 1H),7.25 (m, 1H), 5.7 (dd, 1H), 4.2-3.8 (dd, 1H), 2.2-2.0 (m, 4H) 2.0-1.8(m, 4H). ESMS m/z 329 (M+1).

Step E: Preparation of1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole:A mixture of 4-iodo-1-(2-tetrahydropyranyl) indazole (100 g, 0.304moles), bispinacalotodiborane (96.4 g, 0.381 moles), PdCl₂ (dppf) (8.91g, 0.012 moles) and potassium acetate (85.97 g, 0.905 moles) in DMSO(500 ml) were heated to 80° C. for 2-3 h. After completion, reaction wascooled to r.t and water (1500 ml) was added. Reaction mass was extractedinto ethyl acetate (3×200 ml) and combined organic layers wereevaporated, dried (Na₂SO₄) and concentrated. Crude product was purifiedby column chromatography (silica gel, hexane, 5-10% ethylacetate/hexane) to obtain product 40 as viscous brown oil (70.0 g, 70%).5: ¹H NMR (CDCl₃) δ 8.5 (s, 1H), 7.8 (m, 1H), 7.6 (d, 1H), 7.25 (m, 1H),5.7 (dd, 1H), 4.2-3.8 (dd, 1H), 2.2-2.0 (m, 4H) 2.0-1.8 (m, 4H) 1.4-1.2(s, 12H). ESMS m/z 329 (M+1).

Example 23 Ethyl 5-phenyl-3-ureidofuran-2-carboxylate 41

To a solution of 3-amino-5-phenyl-furan-2-carboxylate ester (116 mg, 1.0eq) in dichloromethane (3 ml) at −78° C. was added chlorosulfonylisocyanate (0.06 ml, 1.3 eq) dropwise (Redman, A. Me.; Dumas, J.; Scott,W. J. Org. Lett. (2000) 2:2061-2063). The reaction was slowly warmed toroom temperature and stirred for 40 minutes. The reaction wasconcentrated. To the residue was added 6N HCl (2.5 ml) and mixture washeated to 100° C. for 20 minutes. Reaction mixture was allowed to cooldown to room temperature, and was neutralized with saturated aq. NaHCO₃.Solid was collected by filtration to yield5-phenyl-3-ureidofuran-2-carboxylate 41 (130 mg, 95%) as a beige solidwhich was used in the next reaction without further purification.

Example 24 6-Phenylfuro[3,2-d]pyrimidine-2,4-diol 42

5-Phenyl-3-ureidofuran-2-carboxylate 41 (125 mg, 1.0 eq) was suspendedin methanol (5 ml) and treated with 1.5 M NaOH (1 ml). Reaction mixturewas heated to reflux for 90 minutes. Reaction mixture was allowed tocool down to room temperature, and was acidified with 6N HCl up to pH 3.Solid was filtered and dried at 95° C. under high vacuum for 24 h toyield 6-phenylfuro[3,2-d]pyrimidine-2,4-diol (79 mg, 76%) as a beigesolid which was used in the next reaction without further purification.

Example 25 2,4-Dichloro-6-phenylfuro[3,2-d]pyrimidine 43

6-phenylfuro[3,2-d]pyrimidine-2,4-diol 42 (80 mg, 1.0 eq) was dissolvedin POCl₃ (2.4 ml). Mixture was cooled to −40° C. andN,N-diisopropylethylamine (0.6 ml) wad slowly added. Reaction mixturewas then heated to reflux for 48 h, then cooled to room temperature. Thereaction mixture was poured into ice/water. Mixture was extracted withethyl acetate. The combined organic layers were washed with saturatedaq. NaHCO₃, dried (Na₂SO₄) and concentrated to yield2,4-dichloro-6-phenylfuro[3,2-d]pyrimidine 43 (76 mg, 82%) which wasused in the next reaction without further purification.

Example 26 2-Chloro-4-morpholino-6-phenylfuro[3,2-d]pyrimidine 44

2,4-Dichloro-6-phenylfuro[3,2-d]pyrimidine 43 (165 mg, 1.0 eq) wassuspended in methanol (4.2 ml) and treated with morpholine (0.22 ml, 4.0eq). Reaction mixture was stirred at room temperature for 4 h. Solid wasfiltered to yield pure2-chloro-4-morpholino-6-phenylfuro[3,2-d]pyrimidine 44 (163 mg, 83%yield) as a beige solid: ¹H NMR (CDCl₃, 400 MHz) δ 7.80 (m, 2H), 7.51(m, 3H), 6.99 (m, 1H), 4.10 (m, 4H), 3.89 (m, 1H); MS (Q1) 316 (M)⁺.

Example 27 2-Chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine 45

To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine 38 (50 mg,1.0 eq) dissolved in THF (2.1 ml) at −78° C. was added 1.6M solution ofn-butyllithium (0.17 ml, 1.3 eq, 1.6M in hexanes). Reaction mixture wasstirred at −78° C. for 30 minutes. A solution of iodine (159 mg, 3.0 eq)in THF (0.6 ml) was added and reaction mixture was allowed to slowlywarm up to room temperature and stirred for 45 minutes. The reactionmixture was quenched with saturated aq. Na₂S₂O₃, and extracted withdichloromethane. The combined organic layers were dried (Na₂SO₄) andconcentrated. The crude reaction mixture was purified by flashchromatography to yield2-chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine 45 (63 mg, 83%): MS(Q1) 366 (M)⁺.

Example 28 2-(2-Chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)propan-2-ol46

To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine 38 (60 mg,1.0 eq) dissolved in THF (2.5 ml) at −78° C. was added 1.6M solution ofn-butyllithium (0.20 ml, 1.3 eq, 1.6M in hexanes). Reaction mixture wasstirred at −78° C. for 30 minutes. Acetone (0.07 ml, 4.0 eq) was addedand reaction mixture was allowed to warm up to −40° C. and stirred for 1h. The crude reaction mixture was concentrated and purified by reversephase HPLC to afford2-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)propan-2-ol 46. MS(Q1) 298 (M)⁺.

Example 293-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylbenzamide101

120 mg of 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19, 62 mgof 3-(N-methylaminocarbonylphenyl)boronic acid and 22 mg ofbis(triphenylphosphine)palladium(II) dichloride in 0.6 mL of 1M Na₂CO₃aqueous solution and 0.6 mL of acetonitrile was heated to 100° C. in asealed microwave reactor for 15 min. The mixture was diluted with H₂Oand then extracted with ethyl acetate (3×20 mL). The combined organiclayers were concentrated. The crude product was purified by reversephase HPLC to give 75 mg of3-(2-chloro-4-morpholinothieno[3,2-d]-6-yl)-N-methylbenzamide.

3-(2-Chloro-4-morpholinothieno[3,2-d]-6-yl)-N-methylbenzamide (50 mg)was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 13.3 mg of 101. MS (Q1) 471 (M)⁺.

Example 302-(1H-indazol-4-yl)-4-morpholino-6-(3-isopropylsulfonylaminophenyl)thieno[3,2-d]pyrimidine102

120 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine,43 μL of isopropylsulfonyl chloride in 1 mL of pyridine was stirredovernight at room temperature. The reaction mixture was evaporated. Thecrude product was purified by reverse phase HPLC to give 47 mg of chlorointermediate.

Chloro intermediate (21 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 10 mg of 102. MS (Q1) 535 (M)⁺

Example 31(S)-1-(2-(1-H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanol103 and(R)-1-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanol104

To 100 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 was addedacetaldehyde via General Procedure D. The crude chloride was subjectedto Procedure A to give a separable mixture of 103 and 104. MS (Q1) 382.2(M)+

Example 322-(1H-indazol-4-yl)-4-morpholino-6-(propylsulfonyl)thieno[2,3-d]pyrimidine105

500 mg of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine was cooled to−78° C. in 50 mL of THF before adding 1.3 eq of a 2.5M solution of nBuLiin hexanes. The reaction was stirred at −78° C. for 30 minutes beforewarming to −40° C. for several minutes to allow for complete formationof the Lithium anion. The reaction was then re-cooled to −78° C. andsulfur dioxide gas was bubbled in via cannula to the reaction solutionfor 2 minutes. The reaction was cooled to 0° C. and quenched with water.The aqueous was extracted with ethyl acetate to remove any2-chloro-4-morpholinothieno[2,3-d]pyrimidine. The aqueous layer was thenlyophilized and purified via reverse phase HPLC to afford 180 mg of pure2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-sulfinic acid.

To 90 mg of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-sulfinic acidin 1.5 mL of DMF was added 1.05 eq of NaH (60% oil dispersion). Thereaction was stirred at room temperature for 30 minutes prior toaddition of 1.05 eq of iodopropane, whereupon the temperature was raisedto 50° C. and the reaction was complete in 30 minutes. The reaction wascooled to room temperature and then extracted into Ethyl Acetate with asaturated bicarbonate solution two times. The organic layer was driedwith MgSO₄, filtered and concentrated to dryness. The crude chloride wassubjected to Procedure A to give 27.6 mg of 105. MS (Q1) 444.1 (M)+.

Example 332-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-1-methoxypropan-2-ol106

200 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 was used alongwith methoxyacetone following General Procedure D to give thecorresponding tertiary alcohol. 60 mg of the crude material was used ina palladium catalyzed cross coupling reaction following generalprocedure A to give 23 mg of 106 after reversed phase HPLC purification.MS (Q1) 426 (M)+

Example 342-(2-(1H-Indazol-4-yl)-4-morpholinofuro[3,2-d]pyrimidin-6-yl)propan-2-ol107

2-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)propan-2-ol (60 mg,1.0 eq) was dissolved in acetonitrile (2.0 ml) and treated with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (123 mg,2.5 eq), PdCl₂(PPh₃)₂ (14.1 mg, 0.10 eq) and 1M potassium acetate (0.6ml). The vial was sealed and heated with stirring in the microwave to140° C. for 30 minutes. The crude reaction mixture was concentrated andpurified by reverse phase HPLC to afford2-(2-(1H-indazol-4-yl)-4-morpholinofuro[3,2-d]pyrimidin-6-yl)propan-2-ol107. MS (Q1) 380 (M)⁺.

2-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-1,3-dimethoxypropan-2-ol108

200 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 was used alongwith 1,3-dimethoxyacetone following General Procedure D to give thecorresponding tertiary alcohol. 60 mg of the crude material was used ina palladium catalyzed cross coupling reaction following generalprocedure A to give 15 mg of 108 after reversed phase HPLC purification.MS (Q1) 456 (M)+

Example 352-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-1-(diethylamino)propan-2-ol109

200 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 was used alongwith (N,N-diethylamino)acetone following general procedure D to give thecorresponding tertiary alcohol. 60 mg of the crude material was used ina palladium catalyzed cross coupling reaction following generalprocedure A to give 12 mg of 109 after reversed phase HPLC purification.MS (Q1) 467 (M)+

Example 361-(4-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)ethanone110

200 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 was used alongwith 1-acetyl-4-piperidone following general procedure D to give thecorresponding tertiary alcohol. The crude reaction mixture wastriturated with acetonitrile and 60 mg of tertiary alcohol was used in apalladium catalyzed cross coupling reaction following general procedureA to give 25 mg of 110 after reversed phase HPLC purification. MS (Q1)479 (M)+

Example 372-(1H-Indazol-4-yl)-6-(3-(methylsulfonyl)phenyl)-4-morpholinofuro[3,2-d]pyrimidine111

2-Chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine (40 mg, 1.0 eq) wasdissolved in acetonitrile (0.4 ml) and treated with3-(methylsulfonyl)phenylboronic acid (23 mg, 1.05 eq), PdCl₂(PPh₃)₂ (7.7mg, 0.10 eq) and 1M Na₂CO₃ (0.33 ml). The vial was sealed and heatedwith stirring in the microwave to 100° C. for 30 minutes. Reactionmixture was quenched with saturated aq. NaHCO₃ and extracted withdichloromethane. The combined organic layers were dried (Na₂SO₄) andconcentrated. The residue was dissolved in acetonitrile (0.4 ml) andtreated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole7 (53 mg, 2.0 eq), PdCl₂(PPh₃)₂ (7.7 mg, 0.10 eq) and 1M Na₂CO₃ (0.33ml). The vial was sealed and heated with stirring in the microwave to150° C. for 15 minutes. The crude reaction mixture was concentrated andpurified by reverse phase HPLC to afford2-(1H-indazol-4-yl)-6-(3-(methylsulfonyl)phenyl)-4-morpholinofuro[3,2-d]pyrimidine111 MS (Q1) 476 (M)⁺.

Example 38N-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxy-2-methylpropanamide112

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (300 mg),3-aminophenylboronic acid (134 mg), andbis(triphenylphosphine)palladium(II) dichloride (55 mg) in 0.6 mL of 1MNa₂CO₃ aqueous solution and 0.6 mL of acetonitrile was heated to 100° C.in a sealed microwave reactor for 15 min. The reaction mixture wasdiluted with ethyl acetate (80 mL), washed with H₂O (50 mL). The organiclayer was dried over MgSO₄, filtered and evaporated to yield 270 mg of3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine.

3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (50 mg)was reacted with 2-hydroxyisobutyric acid via General Procedure I togiveN-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxy-2-methylpropanamine.62 mg of the crudeN-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxy-2-methylpropanaminewas coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 16.2 mg of 112. MS (Q1) 515 (M)⁺.

Example 39(2S)—N-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxypropanamide113

3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (50 mg)was reacted with L-lactic acid via General Procedure I to give(2S)—N-3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxypropanamide.60 mg of the crude(2S)—N-3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxypropanamidewas coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 3 mg of 113. MS (Q1) 501 (M)⁺.

Example 40(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanol114

This compound was prepared from(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanol using theGeneral Procedure A to give 114 after reversed phase HPLC purification(54%). MS (Q1) 368 (M)+

Example 41(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine115

This compound was prepared from(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11, and using the General Procedure A to give 115 after reversedphase HPLC purification (35%). MS (Q1) 367 (M)+

Example 42(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methane(methylsulfonyl)amine116

To a solution of(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine (50 mg,0.2 mmol) in CH₂Cl₂ (4 mL) was added Et₃N (84 μL, 0.6 mmol) and MeSO₂Cl(26 μL, 0.3 mmol). The reaction stirred 18 h at room temperature beforebeing quenched with water (2 mL). The aqueous layer was extracted withEtOAc. The combined organics were dried over Na₂SO₄ and concentrated invacuo. The crude sulfonamide was utilized according to General ProcedureA to provide 116 after reversed phase HPLC purification (13% over 2steps). MS (Q1) 445 (M)+

Example 432-(1H-indazol-4-yl)-4-morpholino-N-(pyridin-3-yl)thieno[3,2-d]pyrimidin-6-amine117

Prepared according to the General Procedure J to give 117 (6% over 2steps). MS (Q1) 430 (M)+

Example 442-(4-(2-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethyl)piperazin-1-yl)-N,N-dimethylacetamide118

Following the procedures of Example 67 to prepare 144, and usingN,N-dimethyl-2-piperazin-1-yl-acetamide, 118 was prepared. NMR: CDCl₃:2.49-2.62 (8H, m, CH₂), 2.68-2.84 (2H, m, CH₂), 2.91 (3H, s, Me), 3.02(3H, s, Me), 3.08 (2H, t, J 7.22, CH₂), 3.13 (2H, s, CH₂), 3.79-3.84(4H, m, CH₂), 3.98-4.02 (4H, m, CH₂), 7.20 (1H, s, Ar), 7.44 (1H, t, J8.0, Ar), 7.52 (1H, d, J 8.15, Ar), 8.22 (1H, d, J 7.35, Ar) and 8.95(1H, s, Ar). MS: (ESI+): MH+ 535.36

Example 45N-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-2-methoxyacetamide119

55 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine was reactedwith 26 mg of methoxyacetyl chloride via General Procedure G to giveN-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-2-methoxyacetamide.

70 mg of crudeN-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-2-methoxyacetamidewas coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 28.1 mg of 119. MS (Q1) 425 (M)⁺

Example 46N-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-methoxyacetamide120

3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (60 mg),methoxyacetyl chloride (23 mg), and 36 μL of triethylamine indichloromethane was stirred for 1 h. The reaction mixture was evaporatedto giveN-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-methoxyacetamide.70 mg of the crudeN-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-methoxyacetamidewas coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 17.3 mg of 120. MS (Q1) 501 (M)⁺.

Example 472-(1H-indazol-4-yl)-4-morpholino-N-(pyridin-2-yl)thieno[3,2-d]pyrimidin-6-amine121

Prepared according to the General Procedure J to give 121 (12% over 2steps). MS (Q1) 430 (M)+

Example 48(2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)(4-methylpiperazin-1-yl)methanone122

45 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylicacid 14 was coupled to 1-methylpiperazine via General Procedure B. Theproduct was purified via reverse phase HPLC to give 34.5 mg of 122. MS(Q1) 464.2 (M)+.

Example 49(2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)(4-hydroxypiperidin-1-yl)methanone123

45 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylicacid 14 was coupled to piperidin-4-ol via General Procedure B. Theproduct was purified via reverse phase HPLC to give 46.6 mg of 123 MS(Q1) 465.1 (M)+.

Example 50(2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)(4-acetylpiperazin-1-yl)methanone124

45 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylicacid 14 was coupled to 1-acetylpiperazine via General Procedure B. Theproduct was purified via reverse phase HPLC to give 52.5 mg of 124. MS(Q1) 492.2 (M)+.

Example 51(2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)(4-methylsulfonylpiperazin-1-yl)methanone125

45 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylicacid 14 was coupled to 1-methanesulfonylpiperazine via General ProcedureB. The product was purified via reverse phase HPLC to give 55 mg of 125.MS (Q1) 528.1 (M)+.

Example 522-(1H-indazol-4-yl)-N-isopropyl-4-morpholinothieno[2,3-d]pyrimidine-6-carboxamide126

45 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylicacid. 14 was coupled to propan-2-amine via General Procedure B. Theproduct was purified via reverse phase HPLC to give 28.1 mg of 126. MS(Q1) 423.2 (M)+.

Example 53N-(2,2,2-trifluoroethyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxamide127

45 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylicacid 14 was coupled to 2,2,2-trifluoroethanamine via General ProcedureB. The product was purified via reverse phase HPLC to give 15 mg of 127.MS (Q1) 463.1 (M)+.

Example 54N-(2-hydroxyethyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxamide128

45 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylicacid 14 was coupled to ethanolamine via General Procedure B. The productwas purified via reverse phase HPLC to give 10.2 mg of 128. MS (Q1)425.1 (M)+.

Example 55N-ethyl-2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxamide129

45 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylicacid 14 was coupled to ethylamine HCl via General Procedure B. Theproduct was purified via reverse phase HPLC to give 31.8 mg of 129. MS(Q1) 409.2 (M)+.

Example 562-(1H-indazol-4-yl)-N,N-dimethyl-4-morpholinothieno[2,3-d]pyrimidine-6-carboxamide130

45 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylicacid 14 was coupled to dimethylamine HCl via General Procedure B. Theproduct was purified via reverse phase HPLC to give 33 mg of 130. MS(Q1) 409.2 (M)+.

Example 572-(1H-indazol-4-yl)-N-methyl-4-morpholinothieno[2,3-d]pyrimidine-6-carboxamide131

45 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylicacid 14 was coupled to methylamine HCl via General Procedure B. Theproduct was purified via reverse phase HPLC to give 36.4 mg of 131. MS(Q1) 395.2 (M)+.

Example 584-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-tetrahydro-2H-thiopyran-4-ol132

250 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 was used alongwith tetrahydrothiopyran-4-one following general procedure D to give thecorresponding tertiary alcohol. The crude reaction mixture wastriturated with acetonitrile to isolate 60 mg of tertiary alcohol thatwas used in a palladium catalyzed cross coupling reaction followinggeneral procedure A to give 35 mg of 132 after reversed phase HPLCpurification. MS (Q1) 454 (M)+

Example 591-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)cyclobutanol133

250 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 was used alongwith cyclobutanone following general procedure D to give thecorresponding tertiary alcohol. 100 mg of the crude material was used ina palladium catalyzed cross coupling reaction following generalprocedure A to give 35 mg of 133 after reversed phase HPLC purification.MS (Q1) 408 (M)+

Example 606-chloro-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine 134

n-Butylithium (1.6 mL, 3.914 mmol) in 2.5 M hexane solution was added toa mixture of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (500 mg,1.957 mmol) in 10 mL of THF at −78° C. The reaction mixture was allowedto warm to −40° C. and stirred for 40 min. A solution ofN-chlorosuccinimide (523 mg, 3.914 mmol) in 8 mL of THF was addeddropwise. After the addition was completed. The reaction mixture wasbrought to room temperature and stirred for 2 h. The reaction wasmonitored by LC/MS. The mixture was diluted with ether and extractedwith 1N HCl (2×60 mL). The aqueous layer was then basified and extractedwith ethyl acetate (2×100 mL). The organic layer was washed with H₂O (60mL), dried over MgSO₄, filtered and evaporated. The crude product waspurified by ISCO Combiflash (5-50% ethyl acetate/hexane) to afford2,6-dichloro-4-morpholinothieno[3,2-d]pyrimidine (284 mg, 50%).

40 mg of 2,6-dichloro-4-morpholinothieno[3,2-d]pyrimidine was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 4.4 mg of 134. MS (Q1) 372 (M)⁺

Example 61(R)-1-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylsulfonyl)propan-2-ol135

607 μL of R-(+) propylene oxide was added to a mixture of 2 g of3-mercaptophenylboronic acid and aluminum oxide (˜30 eq, neutral,activated, ˜150 mesh) in diethyl ether at room temperature. The reactionwas monitored by LC/MS until complete. The mixture was evaporated, andthen added 1N HCl. The resulting mixture was extracted with ethylacetate (3×150 mL). The combined organic layers were dried over MgSO₄,filtered and evaporated to give 3-((R)-2-hydroxypropylthio)phenylboronicacid (1.3, 70%). The crude product was directly used for next stepreaction without purification.

100 mg of 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 wascoupled to 3-((R)-2-hydroxypropylthio)phenylboronic acid via GeneralProcedure I to yield(R)-1-(3-(2-(H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylthio)propan-2-ol.

A solution of 322 mg of oxone in 4 mL H₂O was added to a mixture of 132mg of(R)-1-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylthio)propan-2-olin 8 mL of methanol. The reaction mixture was stirred for 2 h. Themixture was filtered and the filtrate was evaporated. The product waspurified by reverse phase HPLC to yield 3.8 mg of 135. MS (Q1) 536 (M)⁺

Example 62N-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-amino-2-methylpropanamide136

3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (50 mg)was reacted with Boc-2-aminoisobutric acid via General Procedure I togivetert-butyl(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)propan-2-ylcarbamate.75 mg of the crudetert-butyl(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)propan-2-ylcarbamatewas coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yieldtert-butyl(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)propan-2-ylcarbamate.

Tert-butyl(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)propan-2-ylcarbamate(86 mg) was treated with 2 mL of trifluoroacetic acid/dichloromethane(1:1). Upon completion, the reaction mixture was evaporated. The productwas purified by reverse phase HPLC to yield 18.8 mg of 136. MS (Q1) 514(M)+

Example 63N-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-aminoacetamide137

3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (50 mg)was reacted with Boc-glycine via General Procedure I to givetert-butyl(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate.70 mg of the crude tert-butyl(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamatewas coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yieldtert-butyl(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate.

Tert-butyl(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate(82 mg) was treated with 2 mL of trifluoroacetic acid/dichloromethane(1:1). Upon completion, the reaction mixture was evaporated. The productwas purified by reverse phase HPLC to yield 13.9 mg of 137. MS (Q1) 486(M)⁺.

Example 64(S)-1-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylsulfonyl)propan-2-ol138

S-(−) Propylene oxide (152 μL) was added to a mixture of 500 mg of3-mercaptophenylboronic acid and aluminum oxide (˜30 eq, neutral,activated, ˜150 mesh) in diethyl ether at room temperature. The reactionwas monitored by LC/MS until complete. The reaction mixture wasevaporated, and then added 1N HCl. The resulting mixture was extractedwith ethyl acetate (3×50 mL). The combined organic layers were driedover MgSO₄, filtered and evaporated to give3-((S)-2-hydroxypropylthio)phenylboronic acid (414 mg, 90%). The crudeproduct was directly used for next step reaction without purification.

50 mg of 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 wascoupled to 3-((S)-2-hydroxypropylthio)phenylboronic acid via GeneralProcedure I to yield(S)-1-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-g]pyrimidin-6-yl)phenylthio)propan-2-ol.

A solution of 161 mg of oxone in 2 mL H₂O was added to a mixture of 66mg of(S)-1-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylthio)propan-2-olin 4 mL of methanol. The reaction mixture was stirred for 1 h. Themixture was filtered and the filtrate was evaporated. The product waspurified by reverse phase HPLC to yield 3 mg of 138. MS (Q1) 536 (M)+

Example 65N-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxyacetamide139

3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (40 mg)was reacted with glycolic acid via General Procedure I to giveN-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxyacetamine.47 mg of the crudeN-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-hydroxyacetaminewas coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 3 mg of 139. MS (Q1) 487 (M)⁺.

Example 662-(2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)propan-2-ol140

100 mg of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine in 2 mL of THFwas cooled to −78° C. before adding 1.3 eq of 2.5 M nBuLi in hexanessolution. The solution was stirred at −78° C. for 30 minutes beforewarming to −40° C. and adding 10 eq of acetone. The reaction was stirredat −40° C. for 30 minutes then slowly allowed to warm to 0° C. beforequenching with water. The THF was evaporated and the water was extractedwith Ethyl Acetate. The organic layer was dried with MgSO₄, filtered andevaporated. The crude chloride was subjected to Procedure A to give 76mg of 140. MS (Q1) 396.2 (M)+.

Example 672-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylicacid 141 (14)

2-Chloro-4-morpholinothieno[2,3-d]pyrimidine (500 mg) was cooled to −78°C. in 50 mL of THF before adding 1.3 eq of a 2.5M solution of nBuLi inhexanes. The reaction was stirred at −78° C. for 30 minutes beforewarming to −40° C. for several minutes to allow for complete formationof the lithium anion. The reaction was then re-cooled to −78° C. andcarbon dioxide gas evolved from dry ice was bubbled in via cannula tothe reaction solution for 1 hour. The reaction was then slowly warmed to0° C. over 30 minutes and the THF was concentrated by rotovap. Thereaction was then quenched with water and extracted with Ethyl Acetateto remove any 2-chloro-4-morpholinothieno[2,3-d]pyrimidine. The aqueouslayer was then brought to pH of 2-3 by adding concentrated HCl. Theresultant solid that crashed out of the aqueous layer was then collectedby Buchner funnel, rinsed with water and dried overnight under vacuum toyield 494 mg of2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid.

2-Chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid (444 mg)was reacted with 7 via General Procedure A. Upon extraction into EthylAcetate, the product remained in the aqueous layer and was treated with20 eq of Amberlite IR-120 ion-exchange resin for 2 hours or until thesolution became cloudy. The solution was first filtered thru a coarsefilter flask to remove the resin and was then filtered thru a Buchnerfunnel to collect the 476 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylicacid as a light brown solid. 25 mg of this product was then purified viareverse phase HPLC to give 12.8 mg of 141 (14). MS (Q1) 382.1 (M)+.

Example 682-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide142

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid (100 mg)was coupled to ammonium chloride via General Procedure B. The reactionmixture dissolved in Ethyl acetate and extracted with saturated ammoniumchloride solution. The organic layer was concentrated to dryness andsubjected to Procedure A to give 16 mg of 142. MS (Q1) 381.1 (M)+.

Example 696-((3-methoxypropylsulfonyl)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine143

To a mixture of(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol (500mg) and triethylamine (0.5 mL) in dichloromethane (20 mL) at 0° C. wasadded methanesulfonyl chloride (0.27 mL). The reaction mixture wasstirred at room temperature for 16 h and then quenched with water (20mL) and extracted into dichloromethane (2×20 mL). The combined organicswere washed with aqueous brine solution (2×20 mL), dried (MgSO₄) andconcentrated to give methanesulfonic acid2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl ester as ayellow solid (523 mg).

To a solution of methanesulfonic acid2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl ester (300mg) in DMF (8 mL) was added potassium thioacetate (113 mg). The reactionwas stirred at 60° C. for 16 h and then allowed to cool to roomtemperature. The reaction mixture was then quenched with water (20 mL)and extracted into ethyl acetate (2×20 mL). The combined organics werewashed with aqueous brine solution (3×20 mL), dried (MgSO₄),concentrated and purified using column chromatography to give thioaceticacid S-(2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)ester as an off-white solid (210 mg).

To a solution of thioacetic acidS-(2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl) ester(200 mg) in methanol (10 mL) at 0° C. was added a solution of sodiummethoxide (35 mg) in methanol (2 mL). The reaction mixture was stirredat 0° C. for 30 min and then a solution of toluene-4-sulfonic acid3-methoxy-propyl ester (156 mg) in methanol (3 mL) was added dropwise.The reaction mixture was stirred at room temperature for 16 h and thenquenched with water (20 mL) and extracted into ethyl acetate (2×20 mL).The combined organics were washed with aqueous brine solution (2×20 mL),dried (MgSO₄), concentrated and purified using column chromatography togive6-(3-methoxy-propylsulfanylmethyl)-2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidineas a white solid (170 mg).

To a solution of6-(3-methoxy-propylsulfanylmethyl)-2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine(170 mg) in dichloromethane (10 mL) at 0° C. was addedm-chloroperoxybenzoic acid (224 mg) portionwise. The reaction mixturewas stirred at room temperature for 16 h and then quenched with aqueoussodium thiosulfate solution (20 mL) and extracted into dichloromethane(2×20 mL). The combined organics were washed with saturated aqueoussodium hydrogencarbonate solution (2×20 mL) and aqueous brine solution(2×20 mL), dried (MgSO₄) and concentrated to give6-(3-methoxy-propane-1-sulfonylmethyl)-2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidineas a white solid (190 mg).

Suzuki coupling with6-(3-methoxy-propane-1-sulfonylmethyl)-2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine(190 mg) was carried out using the standard method. Purification usingcolumn chromatography gave 143 as a white solid (54 mg). NMR: DMSO:1.92-2.00 (2 H, m, CH₂), 2.18-2.24 (2 H, m, CH₂), 3.22 (3 H, s, Me),3.42 (2 H, t, J 7.22, CH₂), 3.79-3.84 (4 H, m, CH₂), 3.98-4.02 (4 H, m,CH₂), 5.05 (2 H, s, CH₂), 7.44 (1 H, t, J 8.0, Ar), 7.60 (1 H, s, Ar),7.62 (1 H, d, J 8.15, Ar), 8.21 (1 H, d, J 7.35, Ar), 8.85 (1 H, s, Ar)and 13.15 (1 H, s, NH). MS: (ESI+): MH+ 488.14

Example 702-(1H-indazol-4-yl)-4-morpholino-6-(2-(4-methylsulfonylpiperazin-1-yl)ethyl)thieno[3,2-d]pyrimidine144

To a suspension of methoxymethyl triphenylphosphonium chloride (7.24 g)in THF (100 mL) at 0° C. was added n-butyllithium (6.76 mL of a 2.Msolution in hexanes). The reaction mixture was stirred at 0° C. for 1 hand then a suspension of2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (2g) in THF (30 mL) was added dropwise. The reaction mixture was stirredat room temperature for 16 h and then quenched with water (80 mL) andextracted with ethyl acetate (2×80 mL). The combined organics werewashed with aqueous brine solution (2×80 mL), dried (MgSO₄),concentrated and purified using column chromatography to give2-chloro-6-(2-methoxy-vinyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine(mixture of cis/trans isomers) as a yellow solid (2.24 g).

To a solution of2-chloro-6-(2-methoxy-vinyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine(1.05 g) in THF (30 mL) was added 4 N aqueous hydrogen chloride solution(15 mL). The reaction mixture was stirred at 50° C. for 16 h and thenallowed to cool to room temperature. The reaction mixture was dilutedwith water (30 mL) and extracted into ethyl acetate (3×30 mL). Thecombined organics were dried (MgSO₄) and concentrated to give a crudemixture containing(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)acetaldehyde.

To a solution of crude(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-acetaldehyde(300 mg) and 1-methanesulfonyl-piperazine (243 mg) in 1,2-dichloroethane(10 mL) at room temperature was added trimethylorthoformate (0.33 mL).The reaction mixture was stirred at room temperature for 1 h and thensodium triacetoxyborohydride (534 mg) was added. The reaction mixturewas stirred at room temperature for 16 h and then quenched withsaturated aqueous sodium carbonate solution (20 mL) and extracted intodichloromethane (2×20 mL). The combined organics were washed withaqueous brine solution (2×20 mL), dried (MgSO₄), concentrated andpurified using column chromatography to give2-chloro-6-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidineas a white solid (100 mg).

Suzuki coupling with2-chloro-6-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine(100 mg) was carried out using the standard method. Purification usingcolumn chromatography gave 144 as a white solid (24 mg). NMR: CDCl₃:2.54-2.62 (4 H, m, CH₂), 2.71 (3 H, s, Me), 2.72-2.80 (2 H, m, CH₂),3.02-3.11 (2 H, m, CH₂), 3.20-3.28 (4 H, m, CH₂), 3.79-3.84 (4 H, m,CH₂), 3.98-4.02 (4 H, m, CH₂), 7.40 (1 H, s, Ar), 7.44 (1 H, t, J 8.0,Ar), 7.62 (1 H, d, J 8.15, Ar), 8.21 (1 H, d, J 7.35, Ar) and 8.90 (1 H,s, Ar). MS: (ESI+): MH+ 528.24

Example 713-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylpropanamide145

Following the procedures of Example 67b, and using methylamine, 145 wasprepared. NMR: DMSO: 2.52-2.60 (2 H, m, CH₂), 2.61 (3 H, s, Me), 3.18 (2H, t, J 7.22, CH₂), 3.79-3.84 (4 H, m, CH₂), 3.98-4.02 (4 H, m, CH₂),7.30 (1 H, s, Ar), 7.41 (1 H, t, J 8.0, Ar), 7.62 (1 H, d, J 8.15, Ar),7.81-7.84 (1 H, m, NH), 8.21 (1 H, d, J 7.35, Ar), 8.85 (1 H, s, Ar) and13.15 (1 H, s, NH). MS: (ESI+): MH+ 423.18

Example 722-(1H-indazol-4-yl)-6-((methylsulfonyl)methyl)-4-morpholinothieno[3,2-d]pyrimidine146

Following the procedures of Example 67aa, and using methyl iodide, 146was prepared. NMR: DMSO: 3.06 (3 H, s, Me), 3.79-3.84 (4 H, m, CH₂),3.98-4.02 (4 H, m, CH₂), 5.02 (2 H, s, Me), 7.40 (1 H, s, Ar), 7.44 (1H, t, J 8.0, Ar), 7.62 (1 H, d, J 8.15, Ar), 8.21 (1 H, d, J 7.35, Ar),8.85 (1 H, s, Ar) and 13.15 (1 H, s, NH). MS: (ESI+): MH+ 430.10

Example 733-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propanamide147

Following the procedures of Example 67b, and using Ammonium acetate, 147was prepared. NMR: DMSO: 2.54 (2 H, t, J 7.27, CH₂), 3.16 (2 H, t, J7.22, CH₂), 3.79-3.84 (4 H, m, CH₂), 3.98-4.02 (4 H, m, CH₂), 7.40 (1 H,s, Ar), 7.44 (1 H, t, J 8.0, Ar), 7.62 (1 H, d, J 8.15, Ar), 8.21 (H, d,J 7.35, Ar), 8.85 (1 H, s, Ar) and 13.15 (1 H, s, NH). MS: (ESI+): MH+409.15

Example 743-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N,N-dimethylpropanamide148

To solution of triethylphosphonoacetate (2.1 mL) in THF (50 mL) at 0° C.was added sodium hydride (254 mg). The mixture was stirred at 0° C. for1 h and then2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (1.5g) was added. The reaction mixture was stirred at 50° C. for 16 h andthen allowed to cool to room temperature. The reaction was quenched byaddition of water (50 mL) and then filtered to give3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-acrylic acidethyl ester as a yellow solid (1.64 g).

To as solution of3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-acrylic acidethyl ester (2 g) in ethyl acetate (100 mL) was added a suspension ofPd/C (200 mg) in ethanol (10 mL). The flask was flushed with nitrogenand then a hydrogen balloon was fitted. The reaction mixture was stirredat room temperature for 16 h. The mixture was then filtered throughCelite and the filtrate concentrated to give3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)propionic acidethyl ester as a yellow solid (1.83 g).

To a mixture of3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)propionic acidethyl ester (1 g) in methanol (30 mL) was added 1 N aqueous sodiumhydroxide solution (10 mL). The reaction mixture was stirred at roomtemperature for 1 h and then acidified to pH 6 using 2 M aqueoushydrochloric acid. The product was then filtered and washed with waterto give3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-propionic acidas a greenish-yellow solid (612 mg).

A mixture of3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-propionic acid(200 mg), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole(209 mg), 1 M aqueous sodium carbonate solution (1.83 mL) andPdCl₂(PPh₃)₂ (22 mg) in acetonitrile (3 mL) was reacted in the microwaveat 140° C. for 15 min. The reaction mixture was then poured into amixture of ethyl acetate (20 mL) and water (20 mL). The aqueous layerwas collected and carefully acidified to pH 6 using 2 M aqueoushydrochloric acid. The product was then filtered and washed with waterto give3-[2-(1H-indazol-4-yl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl]-propionicacid as a grey solid (145 mg).

To a solution of3-[2-(1H-indazol-4-yl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl]-propionicacid (145 mg) in DMF (5 mL) at room temperature was addedcarbonyldiimidazole (115 mg). The reaction mixture was then stirred atroom temperature for 1 h. Then, triethylamine (0.15 mL) anddimethylamine hydrochloride (58 mg) were added and the solution wasstirred at room temperature for 16 h. The reaction was then quenchedwith water (20 mL) and extracted into ethyl acetate (2×20 mL). Thecombined organics were washed with aqueous brine solution (3×20 mL),dried (MgSO₄), concentrated and purified using column chromatography togive 148 as a white solid (96 mg). NMR: DMSO: 2.68-2.84 (2 H, m, CH₂),2.86 (3 H, s, Me), 3.02 (3 H, s, Me), 3.18 (2 H, t, J 7.22, CH₂),3.79-3.84 (4 H, m, CH₂), 3.98-4.02 (4 H, m, CH₂), 7.40 (1 H, s, Ar),7.44 (1 H, t, J 8.0, Ar), 7.62 (1 H, d, J 8.15, Ar), 8.21 (1 H, d, J7.35, Ar), 8.85 (1 H, s, Ar) and 13.15 (1 H, s, NH). MS: (ESI+): MH+437.22

Example 753-(2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)-1-(4-methylsulfonylpiperazin-1-yl)propanone149

Following the procedures of Example 67b, and using1-methanesulfonyl-piperazine, 149 was prepared. NMR: DMSO: 2.86 (3 H, s,Me), 2.88-2.92 (2 H, m, CH₂), 3.05-3.15 (4 H, m, CH₂), 3.20 (2 H, t, J7.22, CH₂), 3.58-3.63 (4 H, m, CH₂), 3.79-3.84 (4 H, m, CH₂), 3.98-4.02(4 H, m, CH₂), 7.40 (1 H, s, Ar), 7.44 (1 H, t, J 8.0, Ar), 7.62 (1 H,d, J 8.15, Ar), 8.21 (1 H, d, J 7.35, Ar), 8.85 (1 H, s, Ar) and 13.15(1 H, s, NH). MS: (ESI+): MH+ 556.26

Example 762-(1H-indazol-4-yl)-4-morpholino-N-phenylthieno[3,2-d]pyrimidin-6-amine150

Prepared according to the General Procedure J to give 150 (10% over 2steps). MS (Q1) 429 (M)+

Example 773-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenmethylsulfonamide151

50 mg of 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 wascoupled to 3-methylsulfonylaminophenylboronic acid via General ProcedureI. The product was purified by reverse phase HPLC to yield 37.4 mg of151. MS (Q1) 507 (M)⁺.

Example 78N-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-(dimethylamino)acetamide152

55 mg of 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenaminewas reacted with N,N-dimethylglycine via General Procedure I to giveN-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-(dimethylamino)acetamide.70 mg of the crudeN-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-(dimethylamino)acetamidewas coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 3 mg of 152. MS (Q1) 514 (M)⁺.

Example 792-(1H-indazol-4-yl)-6-(3-methoxypyridin-4-yl)-4-morpholinothieno[3,2-d]pyrimidine153

50 mg of 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 wascoupled to 2-methoxypyridine-3-boronic acid via General Procedure I. Theproduct was purified by reverse phase HPLC to yield 7.2 mg of 153. MS(Q1) 445 (M)⁺.

Example 803-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pentan-3-ol154

225 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 was used alongwith 3-propanone following general procedure D to give the correspondingtertiary alcohol. 100 mg of the crude material was used in a palladiumcatalyzed cross coupling reaction following general procedure A to give45 mg of 154 after reversed phase HPLC purification. MS (Q1) 424 (M)+

Example 816-(6-fluoropyridin-3-yl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine155

50 mg of 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 wascoupled to 2-fluoropyridine-5-boronic acid via General Procedure I. Theproduct was purified by reverse phase HPLC to yield 4.7 mg of 155. MS(Q1) 433 (M)⁺.

Example 826-(2-fluoropyridin-3-yl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine156

50 mg of 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 wascoupled to 2-fluoropyridine-3-boronic acid via General Procedure I. Theproduct was purified by reverse phase HPLC to yield 7.3 mg of 156. MS(Q1) 433 (M)⁺.

Example 832-(1H-indazol-4-yl)-6-(4-methoxypyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidine157

50 mg of 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 wascoupled to 4-methoxypyridine-3-boronic acid via General Procedure I. Theproduct was purified by reverse phase HPLC to yield 19.1 mg of 157. MS(Q1) 445 (M)⁺.

Example 843-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine158

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to 3-aminophenylboronic acid via General Procedure I. Theproduct was purified by reverse phase HPLC to yield 14.9 mg of 158. MS(Q1) 429 (M)⁺.

Example 852-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzamide159

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to 2-(aminocarbonylphenyl)boronic acid via General Procedure I.The product was purified by reverse phase HPLC to yield 9.2 mg of 159.MS (Q1) 457 (M)⁺.

Example 86N-(2-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)acetamide160

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to 2-(acetylaminophenyl)boronic acid via General Procedure I.The product was purified by reverse phase HPLC to yield 22.9 mg of 160.MS (Q1) 471 (M)⁺.

Example 873-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzamide161

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to 3-aminocarbonylphenylboronic acid via General Procedure I.The product was purified by reverse phase HPLC to yield 3.9 mg of 161.MS (Q1) 457 (M)⁺.

Example 88N-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propionamide162

Tert-butyl 2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-ylcarbamate(800 mg) was treated with 5 mL of trifluoroacetic acid/dichloromethane(1:1). The reaction mixture was stirred at room temperature untilcomplete. The reaction mixture was evaporated. The residue was dilutedwith ethyl acetate (100 mL), washed with saturated sodium bicarbonate(50 mL) and brine (50 mL). The aqueous layer was back-extracted withethyl acetate (2×60 mL), and then washed with saturated sodiumbicarbonate and brine. The combined organic layers were dried overMgSO₄, filtered and evaporated to afford 580 mg of2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine.

2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (35 mg) was reactedwith 23 μL of propionyl chloride via General Procedure G to giveN-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propionamide.

The crudeN-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propionamide (42 mg)was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 19.8 mg of 162. MS (Q1) 409 (M)⁺

Example 89N-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)acetamide163

2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (40 mg) was reactedwith 21 μL of acetyl chloride via General Procedure G to giveN-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)acetamide.

The crude N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)acetamide(46 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 24.2 mg of 163. MS (Q1) 395 (M)⁺

Example 90N-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)isobutyramide164

2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (35 mg) was reactedwith 27 μL of isobutyryl chloride via General Procedure G to giveN-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)isobutyramide.

The crudeN-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)isobutyramide (45mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 1.9 mg of 164. MS (Q1) 423 (M)⁺

Example 91N-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzamide165

2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (35 mg) was reactedwith 30 μL of benzoyl chloride via General Procedure G to giveN-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzamide.

Crude N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzamide (49mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 8.2 mg of 165. MS (Q1) 457 (M)⁺

Example 923-(1H-indazol-4-yl)-4-morpholino-6-(2-(4-methylsulfonylpiperazin-1-yl)propyl)thieno[3,2-d]pyrimidine166

A mixture of2-(1H-indazol-4-yl)-6-[3-(4-methanesulfonyl-piperazin-1-yl)-prop-1-ynyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidineand 10% Pd/C was stirred overnight under an atmosphere of hydrogen inmethanol and dichloromethane. Purification using flash chromatographyyielded 166. (CDCl3): 2.78-2.82 (4H, m), 2.82 (3H, s), 3.34-3.39 (4H,m), 3.70 (2H, s), 3.92-3.96 (4H, m), 4.07-4.11 (4H, m), 7.52 (1H, dd),7.61-7.65 (2H, m), 8.30 (1H, d, J=7.2), 9.02 (1H, s), 10.10 (1H, br).ESI+: MH+ 538

Example 93(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(4-(methylacetamido)piperidin-1-yl)methanone167

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (45 mg) was coupled to N-methylpiperidine-4-carboxamide viaGeneral Procedure B. The product was purified via reverse phase HPLC togive 26.3 mg of 167. MS (Q1) 506.2 (M)+.

Example 94(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(3-(methylsulfonyl)pyrrolidin-1-yl)methanone168

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (45 mg) was coupled to 3-(methylsulfonyl)pyrrolidine via GeneralProcedure B. The product was purified via reverse phase HPLC to give26.1 mg of 168. MS (Q1) 513.1 (M)+.

Example 952-(1H-indazol-4-yl)-N-(2-(methylsulfonyl)ethyl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide169

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (45 mg) was coupled to 2-(methylsulfonyl)ethanamine via GeneralProcedure B. The product was purified via reverse phase HPLC to give26.8 mg of 169. MS (Q1) 487.1 (M)+.

Example 96N-ethyl-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide170

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (45 mg) was coupled to ethylamine HCl via General Procedure B.The product was purified via reverse phase HPLC to give 10.6 mg of 170.MS (Q1) 409.2 (M)+.

Example 972-(1H-indazol-4-yl)-N-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide171

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (75 mg) was coupled to methylamine HCl via General Procedure B.The product was purified via reverse phase HPLC to give 38.8 mg of 171.MS (Q1) 395.1 (M)+.

Example 98N-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)cyclopropanecarboxamide172

2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (40 mg) was reactedwith 27 μL of cyclopropanecarbonyl chloride via General Procedure G togiveN-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)cyclopropanecarboxamide.

CrudeN-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)cyclopropanecarboxamide(50 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 12.1 mg of 172. MS (Q1) 421 (M)⁺

Example 99N-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-3,3-dimethylbutanamide173

2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (40 mg) was reactedwith 41 μL of tert-butylacetyl chloride via General Procedure G to giveN-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-3,3-dimethylbutanamide.

CrudeN-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-3,3-dimethylbutanamide(55 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 16.9 mg of 173. MS (Q1) 451 (M)⁺

Example 1002-(2-methyl-1H-benzo[d]imidazol-1-yl)-4-morpholinothieno[3,2-d]pyrimidine174

A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 (155mg) and 2-methylbenzimidazole (161 mg) were heated together at 135° C.overnight. The mixture was then cooled, diluted with water and extractedwith ethyl acetate. Combined extracts were dried (Na₂SO₄), filtered andconcentrated. Flash chromatography followed by trituration gave 174(28%). NMR: (CDCl₃): 2.95 (s, 3H, CH₃), 3.89-3.91 (m, 4H, 2×CH₂),4.07-4.09 (m, 4H, 2×CH₂), 7.25-7.28 (m, 2H, 2×ArH), 7.50 (d, H, ArH,J=5.47 Hz), 7.71 (m, H, ArH), 7.85 (d, H, ArH, J=5.48 Hz), 8.09 (m, H,ArH). MS: (ESI+): MH+=352.13

Example 1012-(1H-indazol-4-yl)-6-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)-4-morpholinothieno[3,2-d]pyrimidine175

A mixture of 2-chloro-6-iodo-4-morpholin-4-yl-thieno[3,2-d]pyrimidine19, prepared according to Example 12, (1.57 g), propargyl alcohol (288μL), copper iodide (39 mg), bis(triphenylphosphine)palladium(II)chloride (146 mg), triethylamine (25 ml), and tetrahydrofuran (30 ml)were stirred under nitrogen for 10 days. The reaction mixture was thenpartitioned between chloroform and brine, the combined organics werethen dried (MgSO₄). The solvents were removed in vacuo. The crudeproduct was then purified using flash chromatography to yield3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-yn-1-ol(1.2 g).

To3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-yn-1-ol(142 mg) in chloroform (10 ml) was added triethylamine (77 μL) andmethanesulfonyl chloride (49 μL). Stir at room temperature for 2 hoursthen partition between chloroform and brine, the combined organics weredried (MgSO₄). The solvents were removed in vacuo to yieldmethanesulfonic acid3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-ynylester (150 mg).

A mixture of methanesulfonic acid3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-ynylester (150 mg), potassium carbonate (64 mg), N-methylpiperazine (45 μL)and acetonitrile (5 ml) were stirred at 50° C. for 3 hours. The reactionmixture was then cooled, diluted with dichloromethane, washed withbrine, dried (MgSO₄) and the solvents reduced in vacuo to yield2-chloro-6-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine(101 mg).

Suzuki coupling with2-chloro-6-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidineand indazole 4-boronate ester was carried out using the standardconditions to yield 175 which was purified using flash chromatography.NMR (DMSO): 2.18 (3H, s), 2.30-2.42 (4H, br), 2.50-2.63 (4H, br), 3.68(2H, s), 3.83-3.88 (4H, m), 4.00-4.05 (4H, m), 7.46-7.51 (1H, m), 7.70(1H, d, J=8.3), 7.78 (1H, s), 8.22 (1H, d, J=5.2), 8.88 (1H, s), 13.18(1H, br). ESI+: MH+ 474 (14%)

Example 1022-(1H-indazol-4-yl)-4-morpholino-6-(3-(pyrrolidin-1-yl)prop-1-ynyl)thieno[3,2-d]pyrimidine176

2-(1H-Indazol-4-yl)-4-morpholin-4-yl-6-(3-pyrrolidin-1-yl-prop-1-ynyl)-thieno[3,2-d]pyrimidine176 was prepared by the procedures of Example 93 using pyrrolidine. NMR:(CDCl): 1.88-1.96 (4H, m), 2.72-2.83 (4H, m), 3.70 (2H, s), 3.92-3.96(4H, m), 4.07-4.11 (4H, m), 7.52 (1H, dd), 7.61-7.65 (2H, m), 8.30 (1H,d, J=7.2), 9.02 (1H, s), 10.10 (1H, br). ESI+: MH+ 445

Example 1032-(1H-indazol-4-yl)-4-morpholino-6-(3-morpholinoprop-1-ynyl)thieno[3,2-d]pyrimidine177

2-(1H-Indazol-4-yl)-4-morpholin-4-yl-6-(3-morpholin-4-yl-prop-1-ynyl)-thieno[3,2-d]pyrimidine177 was prepared by the procedures of Example 93 using morpholine. NMR:(CDCl3): 2.65-2.72 (4H, m), 3.62 (2H, s), 3.78-3.82 (4H, m), 3.92-3.96(4H, m), 4.07-4.11 (4H, m), 7.52 (1H, dd), 7.61-7.65 (2H, m), 8.30 (1H,d, J=7.2), 9.02 (1H, s), 10.10 (1H, br). ESI+): MH+ 461

Example 1042-(1H-indazol-4-yl)-4-morpholino-6-(3-(4-methylsulfonylpiperazin-1-yl)thieno[3,2-d]pyrimidine178

2-(1H-Indazol-4-yl)-6-[3-(4-methanesulfonyl-piperazin-1-yl)-prop-1-ynyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-178was prepared by the procedures of Example 93 using1-methanesulfonyl-piperazine. (CDCl3): 2.78-2.82 (4H, m), 2.82 (3H, s),3.34-3.39 (4H, m), 3.70 (2H, s), 3.92-3.96 (4H, m), 4.07-4.11 (4H, m),7.52 (1H, dd), 7.61-7.65 (2H, m), 8.30 (1H, d, J=7.2), 9.02 (1H, s),10.10 (1H, br)

Example 105(2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanol 179

2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehydefrom Experimental 106 was reduced to yield 179. NMR: (400 MHz, CDCl3):8.26 (1H, b, s), 8.18 (1H, d, J 7.36), 7.54 (1H, m), 7.50 (1H, d, J5.02), 7.40 (2H, m), 7.30 (1H, d, J 7.82), 4.99 (2H, d, J 4.75), 4.09(4H, t, J 4.83), 3.91 (4H, t, J 4.82), 2.16 (1H, b, t) MS: (M+H)+ 367.11

Example 1062-(1H-indazol-4-yl)-6-((1-methylpiperidin-4-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine180

Reduction of 181 with Pd/C in methanol-dichloromethane and hydrogen 180.NMR: d4-MeOH: 1.69 (2H, m); 2.2 (3H, m); 2.87 (3H, s); 3.00 (2H, t);3.12 (2H, d, J=6.7 Hz); 3.50 (2H, br d); 4.00 (4H, t, J=4.8 Hz); 4.20(4H, t, J=4.8 Hz); 7.42 (1H, s); 7.60 (1H, t, J=7.7 Hz); 7.77 (1H, d,J=7.4 Hz); 8.92 (1H, s). MS: (ESI+): MH+ 449

Example 1072-(1H-indazol-4-yl)-6-((1-methylpiperidin-4-ylidene)methyl)-4-morpholinothieno[3,2-d]pyrimidine181

A mixture of6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 30 fromExample 9 (1.0 g) and trimethyl phosphate (5 mL) was heated at refluxfor 3 h. After cooling to room temperature, water (20 mL) was added andthe product filtered, washed with water and dried under vacuum to give(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-phosphonicacid dimethyl ester as a yellow solid (0.54 g).

To a suspension of(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-phosphonicacid dimethyl ester (0.80 gm) in THF (10 mL) at −78° C. was addeddropwise lithium diisopropylamide (1.17 mL of a 2.0 M solution inTHF/heptane/ethylbenzene). The mixture was warmed to room temperatureand a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester(0.48 g) in THF (10 mL) was added via cannula. The mixture was thenstirred at room temperature for 2 h, quenched with brine (20 mL) andextracted into dichloromethane (2×20 mL). The combined organics weredried (MgSO₄), reduced in vacuo and purified by column chromatography togive4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethylene)-piperidine-1-carboxylicacid tert-butyl ester as a yellow oil (0.862 g).

To a suspension of4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethylene)-piperidine-1-carboxylicacid tert-butyl ester (0.85 g) in dichloromethane (10 mL) at roomtemperature was added hydrogen chloride (2 mL of a 2.0 M solution indiethyl ether). The reaction mixture was stirred at room temperature for16 h and then reduced in vacuo. The residue was redissolved indichloromethane (10 mL) and washed with saturated sodium carbonatedsolution (2×10 mL) and brine (10 mL), dried (MgSO₄) and reduced in vacuoto give2-chloro-4-morpholin-4-yl-6-piperidin-4-ylidenemethyl-thieno[3,2-d]pyrimidine(0.53 g).

To a mixture of2-chloro-4-morpholin-4-yl-6-piperidin-4-ylidenemethyl-thieno[3,2-d]pyrimidine(500 mg) and formic acid (2.5 mL) at room temperature was addedformaldehyde (0.5 mL of a 37 wt % solution in water). The reactionmixture was stirred at 60° C. for 16 h. The mixture was then dilutedwith dichloromethane (2 mL) and washed with 2 M aqueous sodium hydroxidesolution (20 mL) and brine (20 mL), dried (MgSO₄), reduced in vacuo andpurified by column chromatography to give2-chloro-6-(1-methyl-piperidin-4-ylidenemethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidineas a yellow solid (0.15 g).

2-Chloro-6-(1-methyl-piperidin-4-ylidenemethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidinewas reacted with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in generalprocedure A. Purification on silica yielded 181. NMR: (CDCl₃) 2.37 (3H,s); 2.55 (6H, m); 2.82 (2H, t, J=5.5 Hz); 3.93 (4H, t, J=4.8 Hz); 4.10(4H, t, J=4.8 Hz); 6.44 (1H, s); 7.33 (1H, s); 7.51 (1H, s); 7.60 (1H,d, J=8.2 Hz); 8.28 (1H, d, J=7.1 Hz); 9.03 (1H, s); 10.25 (br s). M+H(447)

Example 1082-(1H-indazol-4-yl)-6-(4-methoxy-1-methylpiperidin-4-yl)-4-morpholinothieno[3,2-d]pyrimidine182

To a solution of4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-4-hydroxy-piperidine-1-carboxylicacid tert-butyl ester (335 mg) in DMF (3 ml) was added sodium hydride(60% w/w suspension in mineral oil, 41 mg) at 0° C. After 30 min,iodomethane (56 ul) was added and the reaction mixture was warmed slowlyto room temperature overnight. Ethyl acetate/brine extraction andpurification on silica afforded.4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-4-methoxy-piperidine-1-carboxylicacid tert-butyl ester (219 mg).

The BOC group was then removed using HCl in ether under standardprocedures to yield2-chloro-6-(4-methoxy-piperidin-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.

To2-chloro-6-(4-methoxy-piperidin-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine(175 mg) in methanol (3 ml) was added formaldehyde (37% solution inwater, 0.11 ml) and sodium borohydride (54 mg). The reaction mixture wasstirred at room temperature overnight. Chloroform/brine extraction andpurification on silica gave2-chloro-4-yl)-6-(4-methoxy-1-methyl-piperidin-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.

Suzuki coupling with2-chloro-4-yl)-6-(4-methoxy-1-methyl-piperidin-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidineand indazole boronate ester was carried out using the standardconditions to give the title compound. NMR: (CDCl3/MeOD): 2.20-2.38 (4H,m), 2.46 (3H, s), 2.55-2.69 (2H, m), 2.80-2.92 (2H, m), 3.22 (3H, s),3.95-4.02 (4H, m), 4.12-4.20 (4H, m), 7.44 (1H, s), 7.56 (1H, m), 7.68(1H, d), 8.20 (1H, d), 8.90 (1H, s) MS: (ESI+): MH+ 465 (10%)

Example 1094-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-1-methylpiperidin-4-ol183

To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4(288 mg) in anhydrous tetrahydrofuran (10 ml), with stirring at −78° C.,was added 2.5M n-butyllithium in hexanes (541 μL). The reaction mixturewas warmed gradually to −40° C. over 1 hour and then cooled to −78oC1-methyl-4-piperidone (138 μL) was then added. The reaction mixture wasgradually warmed to room temperature and then left to stir for 3 days.The reaction mixture was then quenched with water the precipitate formedfiltered. This crude product was then purified using flashchromatography to yield1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methyl-piperidin-4-ol(135 mg).

Suzuki coupling with1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methyl-piperidin-4-ol(135 mg) and indazole boronate ester was carried out using the standardconditions to give 183. NMR (MeOD) 9.00 (1H, s), 8.25 (2H, d), 7.72 (1H,d), 7.60 (1H, t), 7.51 (1H, s), 4.22-4.18 (4H, m), 4.01-3.99 (4H, m),3.27-3.05 (4H, m), 2.82 (3H, s), 2.55-2.48 (2H, m), 2.28-2.20 (2H, m)MH+ 451

Example 110(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-sulfonylmethyl-N-(2-morpholinoethyl)methanamine184

To a solution of 4-(2-aminoethyl)morpholine (0.5 g) in dichloromethane(5 ml) at 0° C. was added methane sulphonyl chloride (0.33 ml) andtriethylamine (0.59 ml) The reaction mixture was warmed to roomtemperature and stirred for 2 hours. The reaction mixture was dilutedwith dichloromethane, the combined organics washed with brine, dried(MgSO₄) and the solvents removed in vacuo to give a crude residue whichwas purified by flash chromatography to yieldN-(2-morpholin-4-yl-ethyl)-methanesulfonamide (596 mg).

To a solution of N-(2-Morpholin-4-yl-ethyl)-methanesulfonamide intetrahydrofuran under nitrogen was added sodium hydride, 60% dispersionin mineral (16 mg). The mixture was stirred at room temperature for 40minutes. A solution of6-Bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (125 mg)in tetrahydrofuran (5 ml) was added. The reaction mixture was stirred atroom temperature for 3.5 hours, then 50° C. for 3.5 hours. The solventswere removed in vacuo to give a crude product which was purified byflash chromatography to yieldN-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(2-morpholin-4-yl-ethyl)-methanesulfonamide(138 mg).

N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(2-morpholin-4-yl-ethyl)-methanesulfonamidewas reacted with4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in generalprocedure A. Purification by flash chromatography on silica yielded 184.NMR: 400 MHz; CDCl3: 2.49 (4H, m); 2.60 (2H, t, J=5.9 Hz); 3.09 (3H, s);3.48 (2H, m); 3.70 (4H, m); 3.92 (4H, m); 4.08 (4H, m); 4.82 (2H, s);7.47 (1H, s); 7.52 (1H, t, J=7.7 Hz); 7.60 (1H, d, J=8.1 Hz); 8.28 (1H,d, J=7.1 Hz); 9.00 (1H, s); 10.15 (1H, br s). MS: (ESI+): 558

Example 111(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylsulfonyl-N-(2-N,N-dimethylaminoethyl)methanamine185

To a solution of N,N-dimethylethylenediamine (0.5 g) in dichloromethane(10 ml) at 0° C. was added triethylamine (0.87 ml) and methane sulphonylchloride. The reaction mixture was warmed to room temperature andstirred for 1 hour. The reaction mixture was partitioned betweendichloromethane and saturated sodium bicarbonate solution, the combinedorganics were dried (MgSO₄) and the solvents removed in vacuo to yield acrude product. This was purified by flash chromatography to yieldN-(2-dimethylamino-ethyl)-methanesulfonamide (0.46 g).

To a solution of N-(2-dimethylamino-ethyl)-methanesulfonamide (50 mg) intetrahydrofuran under nitrogen was added sodium hydride, 60% dispersionin mineral oil, (13 mg). The reaction mixture was stirred at roomtemperature for 30 minutes, the6-Bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine intetrahydrofuran (5 ml) was added dropwise. The reaction mixture wasstirred for 5 days. The solvents were removed in vacuo to give a crudeproduct which was purified by flash chromatography to yieldN-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(2-dimethylamino-ethyl)-methanesulfonamide(35 mg).

N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(2-dimethylamino-ethyl)-methanesulfonamidewas reacted with4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in generalprocedure A. Purification by flash chromatography on silica yielded 185.NMR: 400 MHz; CDCl3: 2.30 (6H, s); 2.55 (2H, m); 3.05 (3H, s); 3.45 (2H,m); 3.94 (4H, t, J=4.8 Hz); 4.10 (4H, t, J=4.8 Hz); 4.82 (2H, s); 7.48(1H, s); 7.52 (1H, t, J=7.8 Hz); 7.60 (1H, d, J=8.3 Hz); 8.28 (1H, d,J=7.3 Hz); 9.02 (1H, s); 10.15 (1H, br s). MS: (ESI+): 516

Example 112(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methyl,N-(3-morpholinopropylsulfonyl)methanamine186

3-Chloro-propane-1-sulfonic acid(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamidewas reacted with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in generalprocedure A. Purification on silica yielded 3-chloro-propane-1-sulfonicacid[2-(1H-indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-methyl-amide.

To a solution of 3-chloro-propane-1-sulfonic acid[2-(1H-indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-methylamide(45 mg) in acetonitrile (2 mL) was added morpholine (38 μL), potassiumcarbonate (18 mg) and potassium iodide (2 mg). the reaction mixture washeated at 80° C. for 72 h and allowed to cool to room temperature beforequenching with water (30 mL) and extracting into dichloromethane (2×30mL). The combined organics were washed with brine (30 mL), dried(MgSO₄), reduced in vacuo and purified by column chromatography to give186 as an off-white solid (27 mg). NMR: CDCl₃: 1.97 (m, 2H), 2.36-2.43(m, 6H), 2.87 (s, 3H), 3.07 (m, 2H), 3.63 (t, J=4.6, 4H), 3.84 (t,J=4.8, 4H), 4.01 (t, J=4.8, 4H), 4.61 (s, 2H), 7.39 (s, 1H), 7.43 (t,J=8.2, 1H), 7.51 (d, J=8.3, 1H), 8.20 (d, J=6.8, 1H), 8.94 (s, 1H),10.30 (brs, 1H). MS: ESI+: MH+ 572.09

Example 113(2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methyl,N-(3-morpholinopropylsulfonyl)methanamine187

3-Chloro-propane-1-sulfonic acid(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amidewas reacted with indole boronic acid in general procedure A.Purification on silica yielded 3-chloro-propane-1-sulfonic acid[2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-methyl-amide.

To a solution of 3-chloro-propane-1-sulfonic acid[2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-methyl-amide(18 mg) in acetonitrile (1 mL) at room temperature was added morpholine(15 μL), potassium carbonate (7 mg) and potassium iodide (2 mg). Thereaction mixture was stirred at 80° C. for 72 h and allowed to cool toroom temperature before quenching with water (30 mL) and extracting intodichloromethane (2×30 mL). The combined organics were washed with brine(30 mL), dried (MgSO₄), reduced in vacuo and purified by columnchromatography to give the title compound as an off-white solid (7 mg).NMR: CDCl₃: 1.96 (m, 2H), 2.43-2.37 (m, 6H), 2.87 (s, 3H), 3.05 (m, 2H),3.84 (t, J=4.8, 4H), 4.01 (t, J=4.8, 4H), 4.60 (s, 2H), 7.21-7.27 (m,2H), 7.39 (s, 1H), 7.42-7.47 (m, 2H), 8.11 (d, J=7.2, 1H), 8.25 (s, 1H).MS: (ESI+): MH+ 571

Example 1142-(1H-indazol-4-yl)-N-(2-methoxyethyl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide188

45 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 was coupled to 2-methoxymethanamine via General Procedure B. Theproduct was purified via reverse phase HPLC to give 18.8 mg of 188. MS(Q1) 439.1 (M)+.

Example 1152-(1H-indol-4-yl)-N-(2-methoxyethyl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide189

To 2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10in dichloromethane (2 ml) was added 2M oxalyl chloride solution indichloromethane (0.75 ml) followed by 2 microdrops of dimethylformamide.The reaction mixture was stirred at room temperature overnight. Thesolvent was removed in vacuo to give a crude product. This crude productwas stirred in dichloromethane (5 ml) and to it was added2-methoxyethylamine (34.8 μL) and triethylamine (61.5 μL). The reactionmixture was stirred at room temperature overnight. It was thenpartitioned between dichloromethane and saturated sodium bicarbonatesolution, the combined organics were dried (MgSO₄) and the solventsremoved in vacuo to give a crude residue. This was purified by flashchromatography to yield2-Methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxylic acid(2-methoxy-ethyl)-amide (30 mg).

2-Methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxylic acid(2-methoxyethyl)-amide was reacted with indole boronic acid in generalprocedure A. Purification on silica yielded 189. NMR: 400 MHz; CDCl₃3.44 (3H, s); 3.60 (2H, m); 3.70 (2H, m); 3.92 (4H, t, J=4.8 Hz); 4.15(4H, t, J=4.8 Hz); 6.74 (1H, br t); 7.30 (1H, d, J=7.8 Hz); 7.35 (1H,m); 7.52 (1H, d, J=8.0 Hz); 7.57 (1H, s); 7.82 (1H, s); 8.20 (1H, d,J=7.4 Hz); 8.30 (1H, br s). MS: (ESI+) M+H (438)

Example 116(2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methyl-N-(2-N,N-dimethylaminosulfonyl)methanamine190

To a solution of(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine(220 mg) in dichloromethane (7 mL) at room temperature was addedtriethylamine (0.174 mL) and then 3-chloropropane sulfonyl chloride(0.134 mL). The reaction mixture was stirred at room temperature for 30min and then quenched with water (25 mL) and extracted intodichloromethane (3×25 mL). The combined organics were washed with brine(30 mL), dried (MgSO₄), reduced in vacuo and purified by columnchromatography to give 3-chloro-propane-1-sulfonic acid(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amide(301 mg).

3-Chloro-propane-1-sulfonic acid(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amidewas reacted with indole boronic acid in general procedure A.Purification on silica yielded 3-chloro-propane-1-sulfonic acid[2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-methyl-amide.

To a solution of 3-chloro-propane-1-sulfonic acid[2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-methyl-amide(59 mg) in acetonitrile (1.0 mL) and DMF (1 mL) was added potassiumcarbonate (19 mg), potassium iodide (19 mg) and a solution of methylamine (26 mg) in acetonitrile (0.5 mL). The reaction mixture was heatedat 60° C. for 12 h and then allowed to cool to room temperature. Thereaction mixture was then purified on silica to give the title compoundas an off-white solid (45 mg). NMR: DMSOd6: 11.2 (1H, s); 8.11 (1H, d,J=7.2 Hz); 7.51 (2H, m); 7.43 (2H, m); 7.19 (H, t, J=7.7 Hz); 4.69 (2H,s); 3.99 (4H, m); 3.82 (4H, m); 3.19 (2H, m) 2.85 (3H, s); 2.32 (2H, m);2.13 (6H, s); 1.86 (2H, m). MS: (ESI+): MH+ 529.2

Example 1172-(1H-indol-4-yl)-6-(2-(methylsulfonyl)ethyl)-4-morpholinothieno[3,2-d]pyrimidine191

2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (200mg), 4-indole-boronic acid (125 mg), sodium hydrogen carbonate (178 mg)and PdCl₂(PPh₃)₂ (4 mg) in toluene (1.5 ml), ethanol (0.75 ml) and water(0.4 ml) were heated in a microwave at 120° C. for 45 min.Chloroform/water extraction and purification on silica gave2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde(257 mg).

To a suspension of2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde(54 mg) in anhydrous methanol (8 ml) was added phosphorus sulphone (34mg), followed by sodium methoxide (148 ul). The reaction mixture wasstirred at room temperature for 4.5 hours, then evaporated onto silicaand purified by flash chromatography to give2-(1H-indol-4-yl)-6-((E)-2-methanesulfonyl-vinyl))-4-morpholin-4-yl-thieno[3,2-d]pyrimidine(30 mg).

2-(1H-Indol-4-yl)-6-((E)-2-methanesulfonyl-vinyl))-4-morpholin-4-yl-thieno[3,2-d]pyrimidine(25 mg) was hydrogenated under atmospheric pressure using 10% palladiumon carbon in MeOH and hydrogen balloon. Purification on silica gave 191.NMR: 400 MHz CDCl3 8.27 (1H, s): 8.19 (1H, d, J=7.4); 7.52 (2H, m); 7.33(3H, m); 4.08 (4H, m); 3.91 (4H, m); 3.49 (4H, m); 2.94 (3H, s). MS:MH+=443.02

Example 118N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-methylacetamide192

Following the procedure of Example 106 to prepare 193,N-[2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-N-methyl-acetamidewas reacted with4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in generalprocedure A. Purification on silica yielded 192. NMR: 400 MHz; CDCl₃2.20, 2.27 (3H, s, 2 rotamers); 3.07 (3H, s); 3.90 (4H, m); 4.05 (4H,m); 4.82, 4.86 (2H, s, 2 rotamers); 7.40 (1H, s); 7.50 (1H, t, J=7.8Hz); 7.60 (1H, d, J=8.2 Hz); 8.28 (1H, d, J=7.2 Hz); 9.00 (1H, s); 10.15(1H, br s). MS: (ESI+): M+H (423)

Example 119N-((2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-methylacetamide193

To 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10(1.0 g) in methanol under nitrogen was added methylamine solution (11.79g methylamine in 50 ml methanol) (1.39 ml). The reaction mixture wasstirred at room temperature overnight. The solvents were then removed invacuo to yield[1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-meth-(E)-ylidene]-methyl-amine.

To[1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-meth-(E)-ylidene]-methyl-amine(0.9 g) in methanol (25 ml) and tetrahydrofuran (10 ml) under nitrogenwas added sodium borohydride (0.17 g) and molecular sieves. The reactionmixture was stirred at room temperature overnight. The solvents wereremoved in vacuo, quenched with brine, extracted with dichloromethane,dried (MgSO₄) and the solvent removed in vacuo to give a crude productwhich was purified using flash chromatography to give(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine(342 mg).

To a solution of(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine(120 mg) in dichloromethane (2 ml) was added acetyl chloride (31.4 μL)and triethylamine (61.6 μL). The reaction mixture was stirred at roomtemperature for 3.5 hours, then diluted with dichloromethane, washedwith brine, dried (MgSO₄) and the solvents removed in vacuo to give acrude residue. This was purified by flash chromatography to yieldN-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-acetamide(110 mg).

N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-acetamidewas reacted with indole boronic acid in general procedure A.Purification on silica yielded 193. NMR: 400 MHz; CDCl₃ 2.10, 2.18 (3H,s, 2 rotamers); 3.00 (3H, s); 3.84 (4H, m); 4.00 (4H, m); 4.73, 4.77(2H, s, 2 rotamers); 7.26 (2H, m); 7.33 (1H, s); 7.42 (1H, m); 7.48 (1H,s); 8.13 (1H, m); 8.21 (1H, br s). MS: (ESI+): M+H (422)

Example 120N-((2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-(methyl)methylsulfonamide194

To a solution of[1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-meth-(E)-ylidene]-methyl-amine(0.76 mmol) in methanol (4 ml) and dichloromethane (4 ml) was addedsodium borohydride (114 mg). The reaction mixture was stirred at roomtemperature overnight. Partitioned between dichloromethane and water.The combined organics were washed with brine, dried (MgSO₄) and thesolvents removed in vacuo to give a crude residue. This was purified byflash chromatography to yieldN-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-methanesulfonamide(85 mg).

N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-methanesulfonamidewas reacted with indole boronic acid in general procedure A.Purification on silica yielded 194. NMR: (400 MHz, DMSO) 2.83 (s, 3H),3.02 (s, 3H), 3.85 (t, J=4.7, 4H), 3.99 (t, J=4.7, 4H), 4.64 (s, 2H),7.19 (t, J=7.7, 1H), 7.43 (m, 2H), 7.51 (m, 2H), 8.12 (d, J=7.3, 1H),11.20 (s br, 1H) MS: (ESI+)[M+H]+ 458.01

Example 121N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-methylsulfonyl-1-methylpyrrolidin-3-amine195

To a solution of (+/−)-3-amino-1N—BOC-pyrrolidine (0.5 g) in MeCN (10mL) was added triethylamine (0.41 mL) then methanesulfonyl chloride(0.22 mL). The mixture was stirred for 2.5 h. An aqueous work-upfollowed by purification on silica gave3-methanesulfonylamino-pyrrolidine-1-carboxylic acid tert-butyl ester(0.49 g).

To a solution of 3-Methanesulfonylamino-pyrrolidine-1-carboxylic acidtert-butyl ester (0.47 g) in DMF (5 mL) was added NaH (63 mg). Themixture was stirred for 40 min. then a solution of6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (0.52 g)in DMF (5 mL) was added via cannular. The resulting mixture was stirredat R.T. for 5 h. An aqueous work-up followed by purification on silicagave3-[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methanesulfonyl-amino]-pyrrolidine-1-carboxylicacid tert-butyl ester (384 mg).

3-[(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methanesulfonyl-amino]-pyrrolidine-1-carboxylicacid tert-butyl ester (380 mg) in CH₂Cl₂ (10 mL) was treat with 2M HClin ether (2 mL). After 18 h the mixture was concentrated to give the HClsalt. This was diluted with saturated sodium bicarbonate solution thenextracted with CH₂Cl₂. Combined extracts were dried (MgSO₄), filteredand concentrated to gave the freebase (204 mg).

A mixture ofN-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-pyrrolidin-3-yl-methanesulfonamide(200 mg), formic acid (2.5 mL) and formaldehyde (37% solution, 0.37 mL)was heated at 60° C. overnight. The mixture was diluted with 2M NaOHthen extracted with CH₂Cl₂. Combined extracts were dried (MgSO₄),filtered and concentrated. Purification on silica yieldedN-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(1-methyl-pyrrolidin-3-yl)-methanesulfonamide(38 mg).

N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(1-methyl-pyrrolidin-3-yl)-methanesulfonamidewas reacted with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in GeneralProcedure A to yield 195. NMR: (CDCl₃): 1.96 (1H, m); 2.19 (2H, m); 2.33(4H, m); 2.48 (1H, m); 2.90 (5H, m); 3.94 (4H, m); 4.10 (4H, m); 4.57(1H, m); 4.90 (2H, s); 7.50 (1H, s); 7.53 (1H, d, J=7.4 Hz); 7.10 (1H,d, J=8.2 Hz); 8.30 (1H, d, J=7.1 Hz); 9.03 (1H, s); 10.14 (1H, br s).MS: (ESI+): MH+=528

Example 1222-(1H-indazol-4-yl)-6-(3-((4-methylsulfonylpiperazin-1-yl)methyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidine196

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (300 mg), 130 mgof 3-formylbenzeneboronic acid and 55 mg ofBis(triphenylphosphine)palladium(II) dichloride in 0.6 mL of 1M Na₂CO₃and 0.6 mL of acetonitrile was heated to 100° C. in the microwavereactor for 15 min. The reaction mixture was diluted with ethyl acetate(60 mL), and then washed with H₂O (40 mL). The organic layer was driedover MgSO₄, filtered and evaporated. The residue was purified by ISCOCombiFlash (0-40% ethyl acetate/hexane) to yield 99 mg of3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzaldehyde.

40 mg of3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzaldehyde, 25 mgof 1-methanesulfonylpiperazine, 35 mg of sodium triacetoxyborohydride in1,2-dichloroethane (1 mL) and acetic acid (10 μL) was stirred overnightat room temperature. The reaction mixture was diluted withdichloromethane (20 mL), and then washed with saturated sodiumbicarbonate (10 mL) and brine (10 mL). The organic layer was dried overMgSO₄, filtered and evaporated to give2-chloro-6-(3-((4-methylsulfonylpiperazin-1-yl)methyl)phenyl)-4-morpholinothieno[3,2d]pyrimidine.

50 mg of the crude2-chloro-6-(3-((4-methylsulfonylpiperazin-1-yl)methyl)phenyl)-4-morpholinothieno[3,2d]pyrimidinewas coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 14.2 mg of 196. MS (Q1) 519 (M)+.

Example 1232-(1H-indazol-4-yl)-6-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidine197

40 mg of3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzaldehyde, 12 mgof 1-methylpiperazine, 28 mg of sodium triacetoxyborohydride in1,2-dichloroethane (1 mL) and acetic acid (10 μL) was stirred overnightat room temperature. The reaction mixture was diluted withdichloromethane (20 mL), and then washed with saturated sodiumbicarbonate (10 mL) and brine (10 mL). The organic layer was dried overMgSO₄, filtered and evaporated to give2-chloro-6-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-4-morpholinothieno[3,2d]pyrimidine.

50 mg of the crude2-chloro-6-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-4-morpholinothieno[3,2d]pyrimidinewas coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 8.5 mg of 197. MS (Q1) 526 (M)⁺.

Example 124 4-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)indolin-2-one 198

To a solution of2-(1H-Indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 199 (90 mg)in acetic acid (2 ml) and water (1 ml) was added pyridinium bromideperbromide (103 mg) as a solution in acetic acid (4 ml) and the reactionmixture was heated to 80° C. for 4 hours. The mixture was then basifiedand extracted into dichloromethane, organic layer was dried (Mg₂SO₄),filtered and volatiles removed in vacuo. Purification on silica yielded198 (23 mg). NMR: (CDCl₃): 3.39-3.43 (4H, m), 4.03-4.08 (4H, m), 4.10(2H, s), 6.95 (1H, d, J=7.4), 7.36 (1H, t, J=7.9), 7.49 (2H, m), 7.79(1H, d, J=5.6), 8.10 (1H, d, J=7.9) MS: (ESI+): MH+ 353 (100%)

Example 125 2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine 199

2-Chloro-4-morpholin-4-yl-thieno-[3.2-d]pyrimidine 4 (120 mg),4-indole-boronic acid (110 mg), sodium hydrogen carbonate (120 mg) andPdCl₂(PPh₃)₂ (30 mg) in DME (3 ml) and water (1 ml) were heated in amicrowave for 90 min at 130° C. Dichloromethane/water extraction andpurification on silica gave 199 (40 mg). NMR: (400 MHz, CDCl₃): 3.95(4H, t, J=4.5), 4.13 (4H, t, J=4.5), 7.30-7.38 (2H, m), 7.52 (1H, d,J=8.1), 7.55-7.59 (2H, m), 7.75 (1H, d, J=5.5), 8.22 (1H, d, J=7.4),8.30 (1H, br) MS: (ESI+): MH+ 337

Example 1262-(1H-indazol-4-yl)-4-morpholino-6-(pyrimidin-5-yl)thieno[3,2-d]pyrimidine200

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to pyrimidine-5-boronic acid via General Procedure I. Theproduct was purified by reverse phase HPLC to yield 19.2 mg of 200. MS(Q1) 416 (M)⁺

Example 1272-(1H-Indazol-4-yl)-4-morpholino-6-phenylfuro[3,2-d]pyrimidine 201

2-Chloro-4-morpholino-6-phenylfuro[3,2-d]pyrimidine 44 (50 mg, 1.0 eq)was dissolved in toluene/ethanol/water (4:2:1, 2.8 ml) and treated with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (97 mg,2.5 eq), PdCl₂(PPh₃)₂ (13.3 mg, 0.12 eq) and sodium carbonate (59 mg,3.5 eq). The vial was sealed and heated with stirring in the microwaveto 150° C. for 25 minutes. The crude reaction mixture was concentratedand purified by reverse phase HPLC to afford 201 MS (Q1) 398 (M)⁺.

Example 128N-(cyclopropylmethoxy)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide202

To 50 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid was added 1 eq cyclopropyl methoxylamine and 4.5 eqN-methylmorpholine in THF at 0° C. After dropwise addition of 1.2 eqdiphenylphosphine at 0° C., the reaction was warmed to room temperatureafter 10 minutes. The reaction was stirred for several hours untilcomplete. Water was added to the reaction mixture which was thenextracted with ethyl acetate. The organic layer was concentrated todryness and subjected to Procedure A to give 22.4 mg of 202. MS (Q1)451.2 (M)+.

Example 1292-(1H-indazol-4-yl)-4-morpholino-6-(1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine203

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolanevia General Procedure I. The product was purified by reverse phase HPLCto yield 18.1 mg of 203. MS (Q1) 404 (M)⁺.

Example 1302-(1H-indazol-4-yl)-4-morpholino-6-phenylthieno[3,2-d]pyrimidine 204

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to phenylboronic acid via General Procedure I. The product waspurified by reverse phase HPLC to yield 17.3 mg of 204. MS (Q1) 414 (M)⁺

Example 131(S)-1-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)propan-2-ol205

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 10 (50 mg)was dissolved in 1 mL of dichloroethane. To this solution was added 2.0equivalents of (s)-1-amino-2-propanol, 0.2 mL of trimethylorthoformate,and 10 μL of acetic acid. The mixture was allowed to stir for 6 hoursprior to adding 1.5 equivalents of sodium triacetoxyborohydride.Following 16 hours of stirring the reaction was poured into saturatedsodium bicarbonate and extracted several times with ethylacetate. Thisintermediate was used crude following the general procedure A to yield205. MS (Q1) 425 (M)+

Example 1322-(1H-indazol-4-yl)-N-(methylsulfonyl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide206

To 50 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid in 1 mL of DMF was added 2 eq of carbonyldiimidazole. The reactionwas stirred for 1 hour at room temperature before addition of a 1 mLsolution containing 2.5 eq DBU and 2 eq of methanesulfonamide in DMF.The reaction was stirred overnight at ambient temperature andconcentrated to dryness. The crude chloride was subjected to Procedure Ato yield 13.8 mg of 206. MS (Q1) 459.1 (M)+.

Example 1336-(isobutylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine207

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added 2-methylpropan-1-amine via General Procedure C.The product was purified via reverse phase HPLC to give 14 mg of 207. MS(Q1) 473.1 (M)+.

Example 1346-(3-hydroxyphenylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine208

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added 3-hydroxyaniline via General Procedure C. Theproduct was purified via reverse phase HPLC to give 10.7 mg of 208. MS(Q1) 509.1 (M)+.

Example 1356-((4-piperazin-2-one)sulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine209

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added piperazin-2-one via General Procedure C. Theproduct was purified via reverse phase HPLC to give 4.3 mg of 209. MS(Q1) 500.1 (M)+.

Example 1366-(4-methylpiperazinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine210

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added 1-methylpiperazine via General Procedure C. Theproduct was purified via reverse phase HPLC to give 6.5 mg of 210. MS(Q1) 500.1 (M)+.

Example 1376-(2-hydroxymethylpiperidinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine211

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added (piperidin-2-yl)methanol via General Procedure C.The product was purified via reverse phase HPLC to give 4.4 mg of 211.MS (Q1) 515.1 (M)+.

Example 1386-(3-hydroxymethylpiperidinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine212

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added (piperidin-3-yl)methanol via General Procedure C.The product was purified via reverse phase HPLC to give 12.1 mg of 212.MS (Q1) 515.1 (M)+.

Example 1396-(4-hydroxymethylpiperidinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine213

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added (piperidin-4-yl)methanol via General Procedure C.The product was purified via reverse phase HPLC to give 7.1 mg of 213.MS (Q1) 515.1 (M)+.

Example 1406-(4-(2-hydroxyethyl)piperidinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine214

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added 2-(piperazin-1-yl)ethanol via General Procedure C.The product was purified via reverse phase HPLC to give 12.2 mg of 214.MS (Q1) 529.1 (M)+.

Example 1416-(4-(2-hydroxyethyl)piperazinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine215

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added 2-(piperazin-1-yl)ethanol via General Procedure C.The product was purified via reverse phase HPLC to give 215. MS (Q1)530.2 (M)+.

Example 1426-(4-hydroxypiperidinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine216

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added piperidin-4-ol via General Procedure C. Theproduct was purified via reverse phase HPLC to give 6.4 mg of 216. MS(Q1) 501.1 (M)+.

Example 1436-(3-hydroxypyrrolidinesulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine217

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added pyrrolidin-3-ol via General Procedure C. Theproduct was purified via reverse phase HPLC to give 3.3 mg of 217. MS(Q1) 487.1 (M)+.

Example 1446-(2-piperidinylethylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine218

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added 2-(piperidin-1-yl)ethanamine via General ProcedureC. The product was purified via reverse phase HPLC to give 13.6 mg of218. MS (Q1) 528.2 (M)+.

Example 1456-(2-N-morpholinoethylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine219

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added 2-morpholinoethanamine via General Procedure C.The product was purified via reverse phase HPLC to give 7.4 mg of 219.MS (Q1) 530.1 (M)+.

Example 1466-(3-methoxypropylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine220

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added 3-methoxypropan-1-amine via General Procedure C.The product was purified via reverse phase HPLC to give 8.5 mg of 220.MS (Q1) 489.1 (M)+.

Example 1476-(N,N-bis-2-hydroxyethylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine221

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added diethanolamine via General Procedure C. Theproduct was purified via reverse phase HPLC to give 6.9 mg of 221. MS(Q1) 505.1 (M)+.

Example 1486-(2-hydroxyethylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine222

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added ethanolamine via General Procedure C. The productwas purified via reverse phase HPLC to give 3.6 mg of 222. MS (Q1) 461.1(M)+.

Example 1496-(dimethylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine223

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added N,N-dimethylamine HCl via General Procedure C. Theproduct was purified via reverse phase HPLC to give 4.9 mg of 223. MS(Q1) 445.1 (M)+.

Example 1506-(methylaminosulfonyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine224

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added methylamine HCl via General Procedure C. Theproduct was purified via reverse phase HPLC to give 9.6 mg of 224. MS(Q1) 431.1 (M)+.

Example 1512-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-amine 225

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid (1 g),791 μL of diphenylphorylazide, 511 μL of triphenylamine in t-BuOH wasrefluxed for 4 h. Upon completion, the reaction mixture was evaporatedand the residue was dissolved in ethyl acetate (150 mL), and then washedwith saturated sodium bicarbonate (50 mL), 5% citric acid (50 mL) andbrine (60 mL). The organic layer was dried over MgSO₄, filtered andevaporated. The residue was purified by ISCO CombiFlash (0-50% ethylacetate/hexane) to yield tert-butyl2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-ylcarbamate (890 mg, 72%)

Tert-butyl 2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-ylcarbamate (50mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 8.8 mg of 225. MS (Q1) 353 (M)⁺

Example 1522-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-ylamino)ethanol226

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (150 mg),2-oxazolidinone (103 mg), potassium phosphate tribasic (250 mg), copperiodide (7 mg), 4 μL of N,N-dimethylethylenediamine in 2 mL of1,4-dioxane was heated to 100° C. for 15 hr. The reaction mixture wasevaporated and the residue was diluted with ethyl acetate (50 mL),washed with brine, dried over MgSO₄, filtered and evaporated. The crudeproduct was purified on reverse phase HPLC to give2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-ylamino)ethanol as aby-product.

2-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-ylamino)ethanol (28 mg)was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 21 mg of 226. MS (Q1) 397 (M)⁺

Example 153(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-sulfonylmethyl-N-(2-methoxyethyl)methanamine227

To a stirring solution of 2-methoxyethylamine (0.58 ml) indichloromethane (10 ml) was added triethylamine (1.0 ml) andmethanesulphonyl chloride (0.51 ml). The mixture was stirred at roomtemperature overnight. The solvents were removed in vacuo to give acrude product which was purified by flash chromatography to giveN-(2-Methoxy-ethyl)-methanesulfonamide (0.74 g).

To a solution of N-(2-Methoxy-ethyl)-methanesulfonamide (61 mg) intetrahydrofuran (1.5 ml) under nitrogen was added sodium hydride, 60%dispersion in mineral oil, (18 mg). The reaction mixture was stirred atroom temperature for 30 minutes.6-Bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (140 mg)was added. The reaction mixture was stirred at room temperature for 2hours and then 50° C. for 5 hours. The solvents were removed in vacuo togive a crude product. This was purified by flash chromatography to giveN-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(2-methoxy-ethyl)-methanesulfonamide(124 mg).

N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(2-methoxy-ethyl)-methanesulfonamidewas reacted with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in generalprocedure A. Purification buy flash chromatography on silica yielded227. NMR: 400 MHz; CDCl3: 3.00 (3H, s); 3.40 (3H, s); 3.56 (2H.m); 3.60(2H, m); 3.93 (4H, t, J=4.8 Hz); 3.98 (4H, t, J=4.82 Hs); 7.50 (1H, s);7.54 (1H, d, J=4.2 Hz); 7.51 (1H, d, J=8.2 Hz); 9.3 (1H, s); 10.15 (1H,s) MS: (ESI+): 503

Example 1541-(4-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)indolin-1-yl)ethanone 228

To a solution of2-(1H-Indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 199 (100 mg)in acetic acid (2 ml) was added sodium cyanoborohydride (76 mg) and thereaction mixture was heated at 60° C. overnight. The mixture was thenbasified and extracted into dichloromethane, organic layer was dried(Mg₂SO₄), filtered and volatiles removed in vacuo. Flash chromatographyand recrystallization from hot dichloromethane/hexane gave 228 (11 mg).NMR: (DMSOd6): 2.21 (3H, s), 3.70 (2H, t, J=8.6), 3.80-3.86 (4H, m),3.98-4.04 (4H, m), 4.17 (2H, t, J=8.5), 7.30 (1H, t, J=7.9), 7.55 (1H,d, J=5.6), 8.00 (1H, d, J=8.4), 8.25 (1H, d, J=7.8), 8.30 (1H, d, J=5.6)MS: (ESI+): MH+ 381

Example 155 2-(1H-indazol-6-yl)-4-morpholinothieno[3,2-d]pyrimidine 229

A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 (772mg), 3-amino-4-methylbenzeneboronic acid (502 mg), DME (10 mL), water (5mL), sodium carbonate (640 mg) and PdCl₂(PPh₃)₂ (100 mg) was heated toreflux for 16 hours. The reaction mixture was then cooled, diluted withethyl acetate, and reduced in vacuo. The residue was purified usingflash chromatography to yield2-methyl-5-(4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl)-phenylamine(930 mg).

To a solution of2-methyl-5-(4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl)-phenylamine(99 mg) in chloroform (10 mL) and acetic acid (2 mL) was added isoamylnitrite (44 μL). The reaction mixture was stirred for 2 days at roomtemperature. The mixture was then quenched with sodium bicarbonatesolution and extracted in to chloroform and reduced in vacuo. Theresidue was purified using flash chromatography to yield 229. MS: ESIMH+ 338

Example 1564-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-1-((thiazol-2-yl)methyl)piperidin-4-ol230

4-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)piperidin-4-oldihydrochloride salt (250 mg) and 2-thiazole-carboxaldehyde (0.08 ml)were stirred together in 1,2-dichloroethane (3 ml) and triethylamine(0.18 ml) with sodium triacetoxyborohydride (187 mg) at room temperatureovernight. Dichloromethane/brine extraction and purification on silicayielded4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-1-thiazol-2-ylmethyl-piperidin-4-ol(119 mg).

Suzuki coupling with4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-1-thiazol-piperidin-4-oland indazole boronate ester was carried out using the standardconditions to give 230. NMR: (DMSO): 1.86-1.94 (2H, m), 2.10-2.18 (2H,m), 2.60-2.68 (2H, m), 2.75-2.82 (2H, m), 3.84-3.87 (4H, m), 3.90 (2H,s), 4.03-4.06 (4H, m), 7.44-7.46 (1H, m), 7.62-7.69 (2H, m), 7.73 (1H,d), 8.23 (1H, d), 8.90 (1H, s), 13.15 (1H, br) MS: (ESI+): MH+ 534 (44%)

Example 1574-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-1-(methylsulfonyl)piperidin-4-ol231

To solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 (1.22g) in anhydrous tetrahydrofuran (20 ml) stirring at −78° C. was added2.5M n-butyllithium in hexanes (2.3 mL). The reaction mixture was warmedgradually to −40° C. over 1 hour, cooled to −78° C., and1-BOC-4-Piperidone (950 mg) was added. The reaction mixture wasgradually warmed to room temperature and then left to stir for 2 hours,poured into ice/water and extracted into ethyl acetate. After the usualdrying and evaporation of the solvent, the residue was purified by flashchromatography to give4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-4-hydroxy-piperidine-1-carboxylicacid tert-butyl ester.

The BOC group was then removed using HCl in ether under standardprocedures to yield4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-4-oldihydrochloride salt. This was reacted with methanesulfonic acidbenzotriazol-1-yl ester in DMF and triethylamine to give4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-1-methanesulfonyl-piperidin-4-ol.Methanesulfonic acid benzotriazol-1-yl ester was prepared usingconditions described in Tetrahedron Letters, 40(1), pp 117-120, 1999.

Suzuki coupling with4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-1-methanesulfonyl-piperidin-4-oland indazole boronate ester was carried out using the standardconditions to give 231. NMR: (CDCl3/MeOD): 1.95-2.02 (2H, m), 2.08-2.16(2H, m), 2.73 (3H, s), 3.08-3.14 (2H, m), 3.55-3.60 (2H, m), 3.75-3.78(4H, m), 3.98-4.02 (4H, m), 7.28 (1H, s), 7.33-7.38 (1H, m), 7.49-7.52(1H, d), 7.97-8.02 (1H, d), 8.68 (1H, s) MS: (ESI+): MH+ 515 (100%)

Example 1584-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-1-((pyridin-2-yl)methyl)piperidin-4-ol232

4-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)piperidin-4-oldihydrochloride salt (250 mg) and 2-pyridylcarboxaldehyde (0.084 ml)were stirred together in 1,2-dichloroethane (3 ml) and triethylamine(0.18 ml) with sodium triacetoxyborohydride (187 mg) at room temperatureovernight. Dichloromethane/brine extraction and purification on silicayielded4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-1-pyridyl-2-ylmethyl-piperidin-4-ol(204 mg).

Suzuki coupling with4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-1-pyridyl-piperidin-4-oland indazole boronate ester was carried out using the standardconditions to give 232. NMR: (CDCl3): 2.05-2.11 (2H, m), 2.29-2.38 (2H,m), 2.70-2.78 (2H, m), 2.84-2.89 (2H, m), 3.80 (2H, s), 3.95-4.02 (4H,m), 4.15-4.19 (4H, m), 7.29-7.32 (1H, m), 7.42 (1H, s), 7.53-7.58 (1H,m), 7.60 (1H, d), 7.68 (1 h, d), 7.82 (1H, t), 8.20 (1H, d), 8.53 (1H,d), 8.90 (1H, s) MS: (ESI+): MH+ 528 (18%)

Example 1592-(1H-indazol-4-yl)-4-morpholino-6-phenylfuro[3,2-d]pyrimidine 233

2-Chloro-4-morpholino-6-phenylfuro[3,2-d]pyrimidine (50 mg, 1.0 eq) wasdissolved in toluene/ethanol/water (4:2:1, 2.8 ml) and treated with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (97 mg,2.5 eq), PdCl₂(PPh₃)₂ (13.3 mg, 0.12 eq) and sodium carbonate (59 mg,3.5 eq). The vial was sealed and heated with stirring in the microwaveto 150° C. for 25 minutes. The crude reaction mixture was concentratedand purified by reverse phase HPLC to afford 233 MS (Q1) 398 (M)⁺.

Example 1602-(1H-indazol-4-yl)-6-(methylsulfonyl)-4-morpholinothieno[3,2-d]pyrimidine234

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (2 gm) was cooled to −78°C. in 50 mL of THF before adding 1.3 eq of a 2.5M solution of nBuLi inhexanes. The reaction was stirred at −78° C. for 30 minutes beforewarming to −40° C. for several minutes to allow for complete formationof the Lithium anion. The reaction was then re-cooled to −78° C. andsulfur dioxide gas was bubbled in via cannula to the reaction solutionfor 2 minutes. 5 mL of the reaction mixture was removed via syringe andquenched into a saturated ammonium chloride solution. This intermediatewas extremely water soluble and had to be purified via reverse phaseHPLC to afford 130 mg of pure2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfinic acid.

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfinic acidin 1.5 mL of DMF was added 1.05 eq of NaH (60% oil dispersion). Thereaction was stirred at room temperature for 30 minutes prior toaddition of 1.05 eq of iodomethane, whereupon the temperature was raisedto 70° C. and the reaction was complete in 30 minutes. The reaction wascooled to room temperature and then extracted into ethyl acetate with asaturated bicarbonate solution which was back-extracted one time withethyl acetate. The organic layers were combined, dried with MgSO₄,filtered and concentrated to dryness. The crude chloride was subjectedto Procedure A to give 22 mg of 234. MS (Q1) 416.1 (M)+.

Example 1612-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol235

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (200 mg) was reacted withacetone following general procedure D to give the corresponding tertiaryalcohol. 120 mg of this crude material was used in a palladium catalyzedcross coupling reaction following general procedure A to give 68 mg of235 after reversed phase HPLC purification. MS (Q1) 396 (M)+

Example 1622-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-(N-phenylsulfonyl)carboxamide236

To 50 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid in 1 mL of THF was added 1.1 eq of carbonyldiimidazole. Thereaction was stirred for 15 minutes at room temperature before additionof a 1 mL solution containing 2 eq DBU and 2 eq of benzenesulfonamide inTHF. The reaction was stirred overnight at ambient temperature andextracted into 0.1N HCl and DCM. The organic layer was concentrated andsubjected to Procedure A to give 11.6 mg of 236. MS (Q1) 520.7 (M)+.

Example 163(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)methanol237

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to 3-hydroxymethylphenylboronic acid via General Procedure I.The product was purified by reverse phase HPLC to yield 14.3 mg of 237.MS (Q1) 444 (M)⁺.

Example 164N-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)acetamide238

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to 3-acetylaminophenylboronic acid via General Procedure I. Theproduct was purified by reverse phase HPLC to yield 24.1 mg of 238. MS(Q1) 471 (M)⁺

Example 1652-(1H-indazol-4-yl)-4-morpholino-6-(pyridin-4-yl)thieno[3,2-d]pyrimidine239

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to 4-pyridineboronic acid via General Procedure I. The productwas purified by reverse phase HPLC to yield 8.6 mg of 239. MS (Q1) 415(M)⁺

Example 1662-(1H-indazol-4-yl)-4-morpholino-6-(pyridin-3-yl)thieno[3,2-d]pyrimidine240

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to 3-pyridineboronic acid via General Procedure I. The productwas purified by reverse phase HPLC to yield 19.7 mg of 240. MS (Q1) 415(M)⁺

Example 1672-(1H-indazol-4-yl)-6-(3,4-dimethoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidine241

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to 3,4-dimethoxyphenylboronic acid via General Procedure I. Theproduct was purified by reverse phase HPLC to yield 35.3 mg of 241. MS(Q1) 474 (M)⁺

Example 1682-(1H-indazol-4-yl)-4-morpholino-6-(4-acetyl-piperazinosulfonyl)thieno[3,2-d]pyrimidine242

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added 1-acetylpiperazine via General Procedure C. Theproduct was purified via reverse phase HPLC to give 32.9 mg of 242. MS(Q1) 527.7 (M)+

Example 1692-(1H-indazol-4-yl)-4-morpholino-6-(4-methylsulfonyl-piperazinosulfonyl)thieno[3,2-d]pyrimidine243

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine (2 gm) 4 was cooled to −78°C. in 50 mL of THF before adding 1.3 eq of a 2.5M solution of nBuLi inhexanes. The reaction was stirred at −78° C. for 30 minutes beforewarming to −40° C. for several minutes to allow for complete formationof the lithium anion. The reaction was then re-cooled to −78° C. andsulfur dioxide gas was bubbled in via cannula to the reaction solutionfor 2 minutes. The reaction was slowly warmed to 0° C. and 5 eq ofn-chlorosuccinmide were added and the reaction was stirred at roomtemperature until complete. The THF was evaporated by rotovap and thenthe reaction was quenched with water. The resultant solid that crashedout of the aqueous layer was then collected by Buchner funnel, rinsedwith water and dried overnight under vacuum to yield 2.4 g of2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonyl chloride 17 as abrown solid.

To 40 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonylchloride 17 was added 1-methansulfonylpiperazine via General ProcedureC. The product was purified via reverse phase HPLC to give 10.7 mg of243. MS (Q1) 563.6 (M)+

Example 170(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone244

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to 2-(piperazin-1-yl)ethanol via GeneralProcedure B. The product was purified via reverse phase HPLC to give20.7 mg of 244. MS (Q1) 493.8 (M)+

Example 171N-benzyl-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide245

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to benzylamine via General Procedure B. Theproduct was purified via reverse phase HPLC to give 8.9 mg of 245. MS(Q1) 470.8 (M)+

Example 172N-(3-hydroxyphenyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide246

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to 3-hydroxyaniline via General Procedure B.The product was purified via reverse phase HPLC to give 7.7 mg of 246.MS (Q1) 472.7 (M)+

Example 1732-(1H-indazol-4-yl)-4-morpholino-N-phenylthieno[3,2-d]pyrimidine-6-carboxamide247

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to aniline via General Procedure B. Theproduct was purified via reverse phase HPLC to give 6.4 mg of 247. MS(Q1) 456.8 (M)+.

Example 174N-((dimethylcarbamoyl)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide248

N-Cbz Glycine (9.6 mmol) was dissolved in DMF (30 mL).Diisopropylethylamine (40 mmol), EDC HCl (10 mmol), HOAt (10 mmol) anddimethylamine hydrochloride (10 mmol) were subsequently added to thesolution. The reaction was allowed to stir overnight. Ethyl acetate (100mL) was added to the solution and the organic was washed with 1 N HClfollowed by a wash with an aqueous solution of saturated sodiumbicarbonate. The organic layer was dried with magnesium sulfate andconcentrated to give 1.02 g of 2-(benzylamino)-N,N-dimethylacetamide.2-(benzylamino)-N,N-dimethylacetamide (4.3 mmol) was dissolved inmethanol (20 mL) and combined with 5% loaded Pd/C (0.21 mmol). Thesolution was stirred under a hydrogen filled balloon for four hours thenfiltered through celite and concentrated to give 402 mg of2-amino-N,N-dimethylacetamide as a yellow oil.

30 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 was coupled to 2-amino-N,N-dimethylacetamide via GeneralProcedure B. The product was purified via reverse phase HPLC to give 6.5mg of 248. MS (Q1) 465.8 (M)+.

Example 175(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone249

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to 4-(pyrrolidin-1-yl)piperidine via GeneralProcedure B. The product was purified via reverse phase HPLC to give13.2 mg of 249. MS (Q1) 517.8 (M)+.

Example 176(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(piperazin-2-one)methanone250

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to piperazin-2-one via General Procedure B.The product was purified via reverse phase HPLC to give 16.4 mg of 250.MS (Q1) 463.7 (M)+.

Example 177(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(4-hydroxypiperidin-1-yl)methanone251

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to piperidin-4-ol via General Procedure B.The product was purified via reverse phase HPLC to give 12.9 mg of 251.MS (Q1) 464.8 (M)+.

Example 178(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(morpholino)methanone252

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to morpholine via General Procedure B. Theproduct was purified via reverse phase HPLC to give 8.7 mg of 252. MS(Q1) 450.8 (M)+.

Example 179(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(3-(methylamino)pyrrolidin-1-yl)methanone253

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to N-methylpyrrolidin-3-amine via GeneralProcedure B. The product was purified via reverse phase HPLC to give16.7 mg of 253. MS (Q1) 463.8 (M)+.

Example 180N-(2,2,2-trifluoroethyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide254

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to 2,2,2-trifluoroethanamine via GeneralProcedure B. The product was purified via reverse phase HPLC to give10.4 mg of 254. MS (Q1) 462.7 (M)+.

Example 1812-(1H-indazol-4-yl)-4-morpholino-N-(2-morpholinoethyl)thieno[3,2-d]pyrimidine-6-carboxamide255

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to 2-morpholinoethanamine via GeneralProcedure B. The product was purified via reverse phase HPLC to give 22mg of 255. MS (Q1) 493.8 (M)+.

Example 1822-(1H-indazol-4-yl)-N-isobutyl-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide256

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to 2-methylpropan-1-amine via GeneralProcedure B. The product was purified via reverse phase HPLC to give13.2 mg of 256. MS (Q1) 436.8 (M)+.

Example 1832-(1H-indazol-4-yl)-4-morpholino-N-(2-(piperidin-1-yl)ethyl)thieno[3,2-d]pyrimidine-6-carboxamide257

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to 2-(piperidin-1-yl)ethanamine via GeneralProcedure B. The product was purified via reverse phase HPLC to give20.4 mg of 257. MS (Q1) 491.8 (M)+.

Example 184N,N-bis(2-hydroxyethyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide258

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to diethanolamine via General Procedure B.The product was purified via reverse phase HPLC to give 15.8 mg of 258.MS (Q1) 468.8 (M)+.

Example 1852-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanol259

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (1 gm) was dissolved in15 mL of THF and cooled to −78° C. in a dry ice acetone bath beforeadding 2.0 mL of 2.5 M nBuLi. The reaction was stirred for 30 min andthen warmed to −40° C. Ethylene oxide was bubbled in to the solution forapproximately 10 min. and the reaction stirred for 2 h at −40° C. It wasthen pored into saturated ammonium chloride and extracted with ethylacetate. After evaporation of the organic layer the crude reaction waschromatographed on 40 g of silica using a 0 to 100% ethyl acetategradient in hexanes to give 333 mg of alcohol. 45 mg of thisintermediate was combined with 36 mg of boronic ester, 0.5 mL ofacetonitrile, 0.5 mL of 1.0 M sodium carbonate and 5 to 10 mg ofPdCl₂(PPh₃)₂ and heated to 140° C. for 10 min. in a microwave reactorand then for an additional 20 min at 145° C. The reaction was extractedwith ethyl acetate and the product was purified on reversed phase HPLCto yield 18 mg of 259. MS (Q1) 382 (M)+

Example 186N-(1-hydroxypropan-2-yl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide260

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to 2-aminopropan-1-ol via General ProcedureB. The product was purified via reverse phase HPLC to give 22.3 mg of260. MS (Q1) 438.8 (M)+.

Example 187(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(4-methylpiperazin-1-yl)methanone261

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to 1-methylpiperazine via General ProcedureB. The product was purified via reverse phase HPLC to give 17.6 mg of261. MS (Q1) 561.8 (M)+.

Example 188(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(4-methylsulfonylpiperazin-1-yl)methanone262

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to 1-methanesulfonylpiperazine via GeneralProcedure B. The product was purified via reverse phase HPLC to give19.2 mg of 262. MS (Q1) 527.7 (M)+.

Example 1892-(1H-indazol-4-yl)-N,N-dimethyl-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide263

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to N,N-dimethylamine HCl via GeneralProcedure B. The product was purified via reverse phase HPLC to give19.7 mg of 263. MS (Q1) 408.8 (M)+.

Example 1902-(1H-indazol-4-yl)-6-(4-(methylsulfonyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidine264

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to 4-methylsulfonylphenylboronic acid via General Procedure I.The product was purified by reverse phase HPLC to yield 10.1 mg of 264.MS (Q1) 492 (M)⁺.

Example 1912-(1H-indazol-4-yl)-6-(3-(methylsulfonyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidine265

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to 3-methylsulfonylphenylboronic acid via General Procedure I.The product was purified by reverse phase HPLC to yield 26.5 mg of 265.MS (Q1) 492 (M)⁺.

Example 192N-(2-hydroxyethyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide266

2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 (30 mg) was coupled to ethanolamine HCl via General Procedure B.The product was purified via reverse phase HPLC to give 6.3 mg of 266.MS (Q1) 424.8 (M)+.

Example 193(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(4-acetylpiperazin-1-yl)methanone267

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (2.5 g) was cooled to−78° C. in 50 mL of THF before adding 1.3 eq of a 2.5M solution of nBuLiin hexanes. The reaction was stirred at −78° C. for 30 minutes beforewarming to −40° C. for several minutes to allow for complete formationof the Lithium anion. The reaction was then re-cooled to −78° C. andcarbon dioxide gas evolved from dry ice was bubbled in via cannula tothe reaction solution for 1 hour. The reaction was then slowly warmed to0° C. over 30 minutes and the THF was concentrated by rotovap. Thereaction was then quenched with water and extracted with Ethyl Acetateto remove any 2-chloro-4-morpholinothieno[3,2-d]pyrimidine. The aqueouslayer was then brought to pH of 2-3 by adding concentrated HCl. Theresultant solid that crashed out of the aqueous layer was then collectedby Buchner funnel, rinsed with water and dried overnight under vacuum toyield 2.65 g of2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid. 500 mgof this intermediate was then subjected to Procedure A. Upon extractioninto Ethyl Acetate, the product remains in the aqueous layer and istreated with 20 eq of Amberlite IR-120 ion-exchange resin for 2 hours oruntil the solution becomes cloudy. The solution is first filtered thru acoarse Filter Flask to remove the resin and is then filtered thru aBuchner funnel to collect the 637 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 as a light brown solid.

30 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylicacid 13 was coupled to 1-acetylpiperazine via General Procedure B. Theproduct was purified via reverse phase HPLC to give 16.8 mg of 267. MS(Q1) 491.8 (M)+.

Example 194(4-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)methanol268

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to 4-hydroxymethylphenylboronic acid via General Procedure I.The product was purified by reverse phase HPLC to yield 20.7 mg of 268.MS (Q1) 444 (M)+.

Example 1951-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-2-methylpropan-2-ol269

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (200 mg) was dissolved in3 mL of THF and cooled to −78° C. in a dry ice acetone bath beforeadding 0.33 mL of 2.5 M nBuLi. The reaction was stirred for 30 min andthen warmed to −40° C. for 20 min and then recooled to −78° C. 0.08 mLof 1,2-epoxy-2-methylpropane was added to the solution and it was slowlywarmed to 0° C. over 1 h at which point the reaction turned brownish. Itwas then pored into saturated ammonium chloride and extracted with ethylacetate. After evaporation of the organic layer the crude reaction waschromatographed silica using a 0 to 100% ethyl acetate gradient inhexanes to give 35 mg of alcohol. This intermediate was combined with 40mg of boronic ester, 0.5 mL of acetonitrile, 0.5 mL of 1.0 M sodiumcarbonate and 5 to 10 mg of PdCl₂(PPh₃)₂ and heated to 140° C. for 10min. in a microwave reactor. The reaction was extracted with ethylacetate and purified on reversed phase HPLC to yield 27 mg of 269. MS(Q1) 410 (M)+

Example 196 2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine 270

To a solution of 3-bromo-2-methylaniline (1.00 g) in dioxane (15 mL) wasadded triethylamine (3.0 mL), Pd(OAc)₂ (60 mg),2-dicyclohexylphosphinobiphenyl (377 mg) and pinacol borane (2.34 mL)and the reaction mixture was heated to 80° C. for 1 hour. The reactionmixture was then cooled, diluted with ethyl acetate, and reduced invacuo. The residue was purified using flash chromatography to yield2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(1.07 g).

Reaction of2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylaminewith 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine under Suzukiconditions yielded2-methyl-3-(4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl)-phenylamine.To a solution of2-methyl-3-(4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl)-phenylamine(80 mg) in chloroform (8 mL) and acetic acid (4 mL) was added isoamylnitrite (36 μL). The reaction mixture was stirred for 1 day at roomtemperature. The mixture was then quenched with sodium bicarbonatesolution and extracted in to chloroform and reduced in vacuo. Theresidue was purified using flash chromatography to yield 270. MS: ESIMH+ 338

Example 197 2-(1H-indol-5-yl)-4-morpholinothieno[3,2-d]pyrimidine 271

2-Chloro-4-moropholinothieno[3.2-d]pyrimidine 4 was reacted with5-indole boronic acid in General Procedure A on a 23.5 mmol scale togive 25.7 mg. of 271 after RP-HPLC purification. MS (Q1) 337.1 (M)+.

Example 198 2-(1H-indol-6-yl)-4-morpholinothieno[3,2-d]pyrimidine 272

2-Chloro-4-moropholinothieno[3.2-d]pyrimidine 4 was reacted with6-indole boronic acid in General Procedure A on a 23.5 mmol scale togive 30 mg. of 272 after RP-HPLC purification. MS (Q1) 337.1 (M)+.

Example 199N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-(methyl)methylsulfonamide273

N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-methanesulfonamidewas reacted with4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in generalprocedure A. Purification on silica yielded 273. NMR: (400 MHz, CDCl₃)10.20 (br s, 1H), 9.02 (br s, 1H), 8.28 (d, J=7.4, 1H), 7.60 (d, J=8.3,1H), 7.51 (t, J=7.7, 1H), 7.47 (s, 1H), 4.67 (s, 2H), 4.09 (t, J=4.8,4H), 3.92 (t, J=4.8, 4H), 2.95 (s, 3H), 2.93 (s, 3H). MS: (ESI+)[M+H]+459.06

Example 200N-[2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-acetamide274

Prepared according to the General Procedure K to give 274. MS (Q1) 409(M)+

Example 201N-[2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-benzamide275

Prepared according to the General Procedure K to give 275. MS (Q1) 471(M)+

Example 202 Pyridine-2-carboxylic acid[2-(1H-indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-amide276

Prepared according to the General Procedure K to give 276. MS (Q1) 472(M)+

Example 203N-[2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-nicotinamide277

Prepared according to the General Procedure K to give 277. MS (Q1) 472(M)+

Example 204N-[2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-isonicotinamide278

Prepared according to the General Procedure K to give 278. MS (Q1) 472(M)+

Example 2053-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-1-(4-methylpiperazin-1-yl)propan-1-one279

Following the procedures to prepare 148, and using N-methyl piperazine,279 was prepared. NMR: DMSO: 2.16 (3 H, s, Me), 2.20-2.28 (4 H, m, CH₂),2.80-2.86 (2H, m, CH₂), 3.19 (2 H, t, J 7.24, CH₂), 3.48-3.50 (4 H, m,CH₂), 3.79-3.84 (4 H, m, CH₂), 3.98-4.02 (4 H, m, CH₂), 7.40 (1 H, s,Ar), 7.44 (1 H, t, J 8.0, Ar), 7.62 (1 H, d, J 8.15, Ar), 8.21 (1 H, d,J 7.35, Ar), 8.85 (1 H, s, Ar) and 13.15 (1 H, s, NH). MS: (ESI+): MH+492.21

Example 2062-(1H-indazol-4-yl)-6-(methoxymethyl)-4-morpholinothieno[3,2-d]pyrimidine280

To a suspension of2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (500mg) in methanol (20 mL) at 0° C. was added sodium borohydride (66 mg).The reaction was stirred for 2 h then quenched with 1:1 saturatedaqueous sodium hydrogencarbonate solution—water (20 mL). The mixture wasstirred for 10 min and then filtered, washed with water and air dried togive (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol asa white solid (489 mg).

To a solution of(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol (300mg) in DMF (10 mL) at 0° C. was added sodium hydride (46 mg). Themixture was stirred for 1 h at 0° C. and then methyliodide (0.07 mL) wasadded. The reaction mixture was stirred at room temperature for 16 h andthen quenched with water (20 mL) and extracted into ethyl acetate (2×20mL). The combined organics were washed with aqueous brine solution (2×20mL), dried (MgSO₄) and concentrated to give2-chloro-6-methoxymethyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as ayellow solid (92 mg).

Suzuki coupling with2-chloro-6-methoxymethyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (85mg) was carried out using the standard method. Purification using columnchromatography gave 280 as a white solid (24 mg). NMR: CDCl₃: 3.41 (3 H,s, Me), 3.81-3.89 (4 H, m, CH₂), 4.01-4.08 (4 H, m, CH₂), 4.70 (2 H, s,CH₂), 7.31 (1 H, s, Ar), 7.42 (1 H, t, J 8.25, Ar), 7.50 (1 H, d, J8.24, Ar), 8.21 (1 H, d, J 7.21, Ar), 8.96 (1 H, s, Ar) and 10.03 (1 H,s, NH). MS: (ESI+): MH+ 382.17

Example 2076-((benzyloxy)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine281

Following the procedures to prepare 280, and using benzyl bromide, 281was prepared. NMR: CDCl₃: 3.88-3.94 (4 H, m, CH₂), 4.09-4.14 (4 H, m,CH₂), 4.69 (2 H, s, CH₂), 4.86 (2 H, s, CH₂), 7.31-7.46 (6 H, m, Ar),7.53 (1 H, t, J 8.22, Ar), 7.56 (1 H, t, J 8.24, Ar), 8.30 (1 H, d, J6.94, Ar), 9.03 (1 H, s, Ar) and 10.11 (1 H, s, NH). MS: (ESI+): MH+458.16

Example 2086-(((pyridin-2-yl)methoxy)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine282

Following the procedures to prepare 280, and using 2-picolyl chloride,282 was prepared. NMR: CDCl₃: 3.80-3.90 (4 H, m, CH₂), 4.01-4.08 (4 H,m, CH₂), 4.72 (2 H, s, CH₂), 4.88 (2 H, s, CH₂), 7.10-7.14 (1 H, m, Ar),7.38 (1 H, s, Ar), 7.40-7.48 (2 H, m, Ar), 7.51 (1 H, d, J 8.23, Ar),7.65 (1 H, t, J 8.22, Ar), 8.18 (1 H, d, J 7.20, Ar), 8.52 (1 H, d, J4.60, Ar), 8.96 (1 H, s, Ar) and 10.06 (1 H, s, NH). MS: (ESI+): MH+459.17

Example 2096-(((pyridin-3-yl)methoxy)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine283

Following the procedures to prepare 280, and using 3-picolyl chloride,283 was prepared. NMR: CDCl₃: 3.90-3.94 (4 H, m, CH₂), 4.08-4.13 (4 H,m, CH₂), 4.68 (2 H, s, CH₂), 4.88 (2 H, s, CH₂), 7.30 (1 H, dd, J 7.79and 4.87, Ar), 7.44 (1 H, s, Ar), 7.51 (1 H, t, J 8.14, Ar), 7.57 (1 H,d, J 8.20, Ar), 7.71 (1 H, d, J 7.79, Ar), 8.28 (1 H, d, J 7.35, Ar),8.58 (1H, dd, J 4.80 and 1.47, Ar), 8.63 (1 H, d, J 1.86, Ar) and 9.02(1 H, s, Ar). MS: (ESI+): MH+ 459.16

Example 2106-(((pyridin-4-yl)methoxy)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine284

Following the procedures to prepare 280, and using 4-picolyl chloride,284 was prepared. NMR: CDCl₃: 3.90-3.94 (4 H, m, CH₂), 4.08-4.13 (4 H,m, CH₂), 4.68 (2 H, s, CH₂), 4.92 (2 H, s, CH₂), 7.30 (2 H, d, J 5.81,Ar), 7.46 (1 H, s, Ar), 7.51 (1 H, t, J 8.14, Ar), 7.60 (1 H, d, J 8.20,Ar), 8.28 (1 H, d, J 7.32, Ar), 8.61 (2 H, d, J 5.27, Ar), 9.01 (1 H, s,Ar) and 10.14 (1 H, s, NH). MS: (ESI+): MH+ 459.17

Example 2112-(1H-indazol-4-yl)-4-morpholino-6-(phenoxymethyl)thieno[3,2-d]pyrimidine285

To a solution of phenol (142 mg) in DMF (8 mL) at 0° C. was added sodiumhydride (64 mg) portionwise. The reaction mixture was stirred at 0° C.for 1 h and then6-bromomethyl-2-chloro-4-morpholin-4-yl-thien[3,2-d]pyrimidine (240 mg)was added. The reaction mixture was stirred at room temperature for 16 hand then quenched with water (20 mL) and extracted into ethyl acetate(2×20 mL). The combined organics were washed with 2 M aqueous sodiumhydroxide solution (2×20 mL) and aqueous brine solution (2×20 mL), dried(MgSO₄) and concentrated to give2-chloro-4-morpholin-4-yl-6-phenoxymethyl-thieno[3,2-d]pyrimidine as awhite solid (123 mg).

Suzuki coupling with2-chloro-4-morpholin-4-yl-6-phenoxymethyl-thieno[3,2-d]pyrimidine (112mg) was carried out using the standard method. Purification using columnchromatography gave 285 as a white solid (34 mg). NMR: CDCl₃: 3.90-3.98(4 H, m, CH₂), 4.08-4.13 (4 H, m, CH₂), 5.41 (2 H, s, CH₂), 6.98-7.06 (3H, m, Ar), 7.40-7.46 (2 H, m, Ar), 7.49-7.55 (2 H, m, Ar), 7.60 (1 H, d,J 8.22, Ar), 8.30 (1 H, d, J 7.24, Ar), 9.01 (1 H, s, Ar), 10.14 (1 H,s, NH). MS: (ESI+): MH+ 444.17

Example 212N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)benzamide286

(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 wasacylated with benzoyl chloride following General Procedure K and thenreacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole7 (34 mg) following General Procedure A to give 286. MS (Q1) 471 (M)+

Example 213N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)picolinamide287

(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 wasacylated with picolinoyl chloride following General Procedure K and thenreacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole7 (34 mg) following General Procedure A to give 287. MS (Q1) 472 (M)+

Example 214N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)nicotinamide288

(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 wasacylated with nicotinoyl chloride following General Procedure K and thenreacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole7 (34 mg) following General Procedure A to give 288. MS (Q1) 472 (M)+

Example 215N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)acetamide289

(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 wasacylated with acetylchloride following General Procedure K and thenreacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole7 (34 mg) following General Procedure A to give 289. MS (Q1) 409 (M)+

Example 216N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)isonicotinamide290

(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 wasacylated with isonicotinoyl chloride following General Procedure K andthen reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (34 mg)following General Procedure A to give 290. MS (Q1) 472 (M)+

Example 2172-(1H-indazol-4-yl)-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide 291

2-Chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide was reactedwith 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to give, after purification by reverse HPLC, 291. MS(Q1) 365 (M⁺)

Example 218(2-(1H-indazol-4-yl)-4-morpholinofuro[3,2-d]pyrimidin-6-yl)(4-N-methylsulfonylpiperazin-1-yl)methanone292

A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylicacid (1.0 eq), HATU (1.5 eq), hydrochloride salt of1-methanesulfonylpiperazine (1.5 eq), diisopropylethylamine (3.0 eq) inDMF was stirred for 30 minutes. The solid that precipitated out from thereaction was filtered to give2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl(4-methylsulfonylpiperazin-1-yl)methanone.MS (Q1) 430 (M)⁺

2-Chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl(4-methylsulfonylpiperazin-1-yl)methanonewas reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to give, after purification by reverse HPLC, 292. MS(Q1) 352 (M⁺)

Example 2192-(1H-indazol-4-yl)-N-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide293

To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine 45 fromExample 27 (1.0 eq) dissolved in THF at −78° C. was added 1.6M solutionof n-butyllithium in hexanes (1.3 eq). Reaction mixture was stirred at−78° C. for 30 minutes. A gentle flow of CO₂ gas was then bubbled in thereaction flask for 1 h at −78° C., then at 0° C. for 40 min. Reactionmixture was concentrated, then quenched with water. Mixture wasextracted with ethyl acetate to remove any starting material remaining.Then, aqueous layer was acificied with HCl 6M up to pH 3. Resultingsolid was filtered to give2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylic acid. MS (Q1)284 (M)+

A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxylicacid (1.0 eq), HATU (1.5 eq), hydrochloride salt of methylamine (1.5eq), diisopropylethylamine (3.0 eq) in DMF was stirred for 30 minutes.Reaction mixture was quenched with saturated aq. NaHCO₃ and extractedwith ethyl acetate. The combined organic layers were dried (Na₂SO₄) andconcentrated. The crude reaction mixture was purified by flashchromatography to give2-chloro-N-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide. MS(Q1) 297 (M)⁺

2-Chloro-N-methyl-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide wasreacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole7 via General Procedure A to give, after purification by reverse HPLC,293. MS (Q1) 379 (M⁺)

Example 220(2-(1H-indazol-4-yl)-4-morpholinofuro[3,2-d]pyrimidin-6-yl)methanol 296

2-Chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carbaldehyde (1.0 eq) wasdissolved in 1,2-dichloroethane and treated with hydrochloride salt of1-methanesulfonylpiperazine (1.4 eq), sodium acetate (1.4 eq) andtrimethyl orthoformate (10 eq). Reaction mixture was stirred at r.t. for12 h. Sodium triacetoxyborohydride (1.2 eq) was added and reactionmixture was stirred at r.t. for 8 h. Reaction mixture was quenched withsaturated aq. NaHCO₃ and extracted with dichloromethane. The combinedorganic layers were dried (Na₂SO₄) and concentrated. The crude reactionmixture was purified by flash chromatography to yield2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)methanol: MS (Q1) 270(M)⁺

2-Chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)methanol was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to give, after purification by reverse HPLC, 296. MS(Q1) 352 (M⁺)

Example 2212-(1H-indazol-4-yl)-6-(4-methoxypyridin-3-yl)-4-morpholinofuro[3,2-d]pyrimidine297

2-Chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine 45 from Example 27 wasreacted with 4-methoxypyridin-3-yl-3-boronic acid via General ProcedureA to give the corresponding intermediate, after purification by flashchromatography, which was then reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to give,after purification by reverse phase HPLC, 297. MS (Q1) 429 (M⁺)

Example 2222-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxamide298

2-Chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid fromExample 67 (100 mg) was treated with 90 mg of ammonium chloride viaGeneral Procedure B to yield2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide. Crudeintermediate 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamidewas then reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 via GeneralProcedure A to give 17.4 mg of 298 after reverse phase HPLCpurification. MS (Q1) 381.1 (M)+

Example 2232-(1H-indazol-4-yl)-4-morpholino-6-(3-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidine299

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)]benzylmorpholine, andthen reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure F. The product was purified by reverse phase HPLC toyield 2.6 mg of 299. MS. (Q1) 513.2 (M)⁺

Example 224 methyl3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-5-aminobenzoate300

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) wascoupled to 3-amino-5-methoxycarbonylphenyl boronic acid, and thenreacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazolevia General Procedure F. The product was purified by reverse phase HPLCto yield 5.2 mg of 300. MS. (Q1) 487.1 (M)⁺

Example 225N-(3-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)phenyl)acetamide301

To a solution of6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added 3-aminoacetanilide(39 mg, 0.3 mmol) and K₂CO₃ (50 mg, 0.4 mmol). The resulting solutionstirred at room temperature overnight then was concentrated in vacuo.The residue was diluted with water and filtered. The crude product wasutilized in a Suzuki coupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide301 after reverse phase HPLC purification (39 mg). MS (Q1) 500 (M)+

Example 226N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)benzenamine302

To a solution of6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added aniline (24 μL, 0.3mmol) and K₂CO₃ (50 mg, 0.4 mmol). The resulting solution stirred atroom temperature overnight then was concentrated in vacuo. The residuewas diluted with water and filtered. The crude product was utilized in aSuzuki coupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide302 after reverse phase HPLC purification (49 mg). MS (Q1) 443 (M)+

Example 2273-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)benzamide303

To a solution of6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added 3-aminobenzamide (35mg, 0.3 mmol) and K₂CO₃ (50 mg, 0.4 mmol). The resulting solutionstirred at room temperature overnight then was concentrated in vacuo.The residue was diluted with water and filtered. The crude product wasutilized in a Suzuki coupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide303 after reverse phase HPLC purification (28 mg). MS (Q1) 486 (M)+

Example 228(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N,N-dimethylmethanamine304

To a solution of6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added dimethylaminehydrochloride (21 mg, 0.3 mmol) and K₂CO₃ (90 mg, 0.6 mmol). Theresulting solution stirred at room temperature overnight then wasconcentrated in vacuo. The residue was diluted with water and filtered.The crude product was utilized in a Suzuki coupling using GeneralProcedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide304 after reverse phase HPLC purification (34 mg). MS (Q1) 395 (M)+

Example 229N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholine-4-carboxamide305

To a solution of(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (50 mg, 0.2 mmol) in CH₂Cl₂ (4 mL) was added Et₃N (84 μL, 0.6mmol) and 4-Morpholinylcarbonyl chloride (40 μL, 0.3 mmol). The reactionstirred 18 h at room temperature before being quenched with water. Theaqueous layer was extracted with EtOAc. The combined organics were driedover Na₂SO₄ and concentrated in vacuo. The crude product was utilized ina Suzuki coupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide305 after reverse phase HPLC purification (24 mg). MS (Q1) 480 (M)+

Example 230(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)N-phenylsulfonylmethanamine306

To a solution of(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (50 mg, 0.2 mmol) in CH₂Cl₂ (4 mL) was added Et₃N (84 μL, 0.6mmol) and benzenesulfonyl chloride (44 μL, 0.3 mmol). The reactionstirred 18 h at room temperature before being quenched with water. Theaqueous layer was extracted with EtOAc. The combined organics were driedover Na₂SO₄ and concentrated in vacuo. The crude product was utilized ina Suzuki coupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide306 after reverse phase HPLC purification (3 mg). MS (Q1) 507 (M)+

Example 2313-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1,1-dimethylurea307

To a solution of(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (50 mg, 0.2 mmol) in CH₂Cl₂ (4 mL) was added Et₃N (84 μL, 0.6mmol) and dimethylcarbamyl chloride (0.3 mmol). The reaction stirred 18h at room temperature before being quenched with water. The aqueouslayer was extracted with EtOAc. The combined organics were dried overNa₂SO₄ and concentrated in vacuo. The crude product was utilized in aSuzuki coupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide307 after reverse phase HPLC purification (12 mg). MS (Q1) 438 (M)+

Example 2321-(2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)ethanol308

2-chloro-4-morpholinothieno[2,3-d]pyrimidine (300 mg) was reacted withacetaldehyde via General Procedure D to give1-(2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)ethanol. This crudeintermediate was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 via GeneralProcedure A to yield 100.2 mg of 308 following reverse phase HPLCpurification. MS (Q1) 382.1 (M)+

Example 2332-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)sulfonamide309

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-sulfonyl chloride 17 wasreacted with ammonium chloride via General Procedure C. The crudeintermediate was then reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 via GeneralProcedure A to give 36.3 mg of 309 following reverse phase HPLCpurification. MS (Q1) 417.1 (M)+

Example 2342-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-amine310

Zirconium(IV) chloride (320 mg) was added to a mixture of 410 mg of2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide inTHF at −10° C. The reaction mixture was stirred for 30 min at −10° C.Methylmagnesium bromide (2.7 mL, 3.0 M in diethyl ether) was added. Thereaction mixture was allowed to warm to room temperature and stirredovernight. Saturated ammonium chloride aqueous solution was added, andthen extracted with ethyl acetate. The organic layer was dried over(MgSO₄) and evaporated to yield2-(2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)propan-2-amine(380 mg).

2-(2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)propan-2-amine(30 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 11.5 mg of 310. MS (Q1) 395.0 (M)⁺

Example 2353-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)oxazolidin-2-one311

To a solution of 2-oxazolidinone (50 mg, 0.6 mmol) in DMF (2 mL) at 0°C. NaH (60% in mineral oil; 0.7 mmol) was added. After 15 minutes,6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (200 mg, 0.6 mmol) in DMF (0.5 mL) was added and the reactionstirred 15 min. The reaction was quenched by the addition of saturatedaqueous ammonium chloride. The aqueous layer was extracted with EtOAc.The combined organics were dried over Na₂SO₄, filtered, and concentratedin vacuo. The crude product was utilized in a Suzuki coupling usingGeneral Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide311 after reverse phase HPLC purification (6 mg). MS (Q1) 437 (M)+

Example 2366-((1H-imidazol-1-yl)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine312

To a solution of6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added imidazole (18 mg,0.3 mmol) and K₂CO₃ (50 mg, 0.4 mmol). The resulting solution stirred atroom temperature overnight then was concentrated in vacuo. The residuewas diluted with water and filtered. The crude product was utilized in aSuzuki coupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide312 after reverse phase HPLC purification (32 mg). MS (Q1) 418 (M)+

Example 2376-((1H-1,2,4-triazol-1-yl)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine313

To a solution of6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added 1,2,4-triazole (18mg, 0.3 mmol) and K₂CO₃ (50 mg, 0.4 mmol). The resulting solutionstirred at room temperature overnight then was concentrated in vacuo.The residue was diluted with water and filtered. The crude product wasutilized in a Suzuki coupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide313 after reverse phase HPLC purification (16 mg). MS (Q1) 419 (M)+

Example 2382-(1H-indazol-4-yl)-6-(methoxymethyl)-4-morpholinothieno[3,2-d]pyrimidine314

To a suspension of2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 fromExample 3 (500 mg) in methanol (20 mL) at 0° C. was added sodiumborohydride (66 mg). The reaction was stirred for 2 h then quenched with1:1 saturated aqueous sodium hydrogencarbonate solution:water (20 mL).The mixture was stirred for 10 min and then filtered, washed with waterand air dried to give(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol as awhite solid (489 mg).

To a solution of(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol (300mg) in DMF (10 mL) at 0° C. was added sodium hydride (46 mg). Themixture was stirred for 1 h at 0° C. and then methyliodide (0.07 mL) wasadded. The reaction mixture was stirred at room temperature for 16 h andthen quenched with water (20 mL) and extracted into ethyl acetate (2×20mL). The combined organics were washed with aqueous brine solution (2×20mL), dried (MgSO₄) and concentrated to give2-chloro-6-methoxymethyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as ayellow solid (92 mg). Suzuki coupling with2-chloro-6-methoxymethyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (85mg) was carried out via General Procedure A. Purification using columnchromatography gave 314 as a white solid (24 mg). NMR: CDCl₃: 3.41 (3 H,s, Me), 3.81-3.89 (4 H, m, CH₂), 4.01-4.08 (4 H, m, CH₂), 4.70 (2 H, s,CH₂), 7.31 (1 H, s, Ar), 7.42 (1 H, t, J 8.25, Ar), 7.50 (1 H, d, J8.24, Ar), 8.21 (1 H, d, J 7.21, Ar), 8.96 (1 H, s, Ar) and 10.03 (1 H,s, NH). MS: (ESI+): MH+ 382.17

Example 2396-((benzyloxy)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine315

Following the procedures for compound 314,(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol in DMFand sodium hydride was alkylated with benzyl bromide to give2-chloro-6-benzyloxymethyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.Suzuki coupling of2-chloro-6-benzyloxymethyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine and7 was carried out via General Procedure A. Purification using columnchromatography gave 315. NMR: CDCl₃: 3.88-3.94 (4 H, m, CH₂), 4.09-4.14(4 H, m, CH₂), 4.69 (2 H, s, CH₂), 4.86 (2 H, s, CH₂), 7.31-7.46 (6 H,m, Ar), 7.53 (1 H, t, J 8.22, Ar), 7.56 (1 H, t, J 8.24, Ar), 8.30 (1 H,d, J 6.94, Ar), 9.03 (1 H, s, Ar) and 10.1 (1 H, s, NH). MS: (ESI+): MH+458.16

Example 2402-(1H-indazol-4-yl)-4-morpholino-6-(phenoxymethyl)thieno[3,2-d]pyrimidine316

To a solution of phenol (142 mg) in DMF (8 mL) at 0° C. was added sodiumhydride (64 mg) portionwise. The reaction mixture was stirred at 0° C.for 1 h and then6-bromomethyl-2-chloro-4-morpholin-4-yl-thien[3,2-d]pyrimidine (240 mg)was added. The reaction mixture was stirred at room temperature for 16 hand then quenched with water (20 mL) and extracted into ethyl acetate(2×20 mL). The combined organics were washed with 2 M aqueous sodiumhydroxide solution (2×20 mL) and aqueous brine solution (2×20 mL), dried(MgSO₄) and concentrated to give2-chloro-4-morpholin-4-yl-6-phenoxymethyl-thieno[3,2-d]pyrimidine as awhite solid (123 mg).

Suzuki coupling of2-chloro-4-morpholin-4-yl-6-phenoxymethyl-thieno[3,2-d]pyrimidine (112mg) and 7 was carried out using the standard method. Purification usingcolumn chromatography gave 316 as a white solid (34 mg). NMR: CDCL₃:3.90-3.98 (4 H, m, CH₂), 4.08-4.13 (4 H, m, CH₂), 5.41 (2 H, s, CH₂),6.98-7.06 (3 H, m, Ar), 7.40-7.46 (2 H, m, Ar), 7.49-7.55 (2 H, m, Ar),7.60 (1 H, d, J 8.22, Ar), 8.30 (1 H, d, J 7.24, Ar), 9.01 (1 H, s, Ar),10.14 (1 H, s, NH). MS: (ESI+): MH+ 444.17

Example 2416-(((pyridin-2-yl)methoxy)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine317

Following the procedures for compound 314,(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol in DMFand sodium hydride was alkylated with 2-picolyl chloride to give4-(2-chloro-6-((pyridin-2-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine.Suzuki coupling of4-(2-chloro-6-((pyridin-2-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholineand 7 was carried out via General Procedure A. Purification using columnchromatography gave 317. NMR: CDCl₃: 3.80-3.90 (4 H, m, CH₂), 4.01-4.08(4 H, m, CH₂), 4.72 (2 H, s, CH₂), 4.88 (2 H, s, —CH₂), 7.10-7.14 (1H,m, Ar), 7.38 (1 H, s, Ar), 7.40-7.48 (2 H, m, Ar), 7.51 (1 H, d, J 8.23,Ar), 7.65 (1 H, t, J 8.22, Ar), 8.18 (1 H, d, J 7.20, Ar), 8.52 (1 H, d,J 4.60, Ar), 8.96 (1 H, s, Ar) and 10.06 (1 H, s, NH). MS: (ESI+): MH+459.17

Example 2424-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-7-(thiazol-5-yl)thieno[3,2-d]pyrimidine318

2-Chloro-4-morpholin-4-yl-7-thiazol-5-yl-thieno[3,2-d]pyrimidine and5-(4,4,5,5-tetramethyl-[1.3.2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridinewere reacted according to General Procedure A to give 318. NMR (DMSO,400 MHz), 3.86 (4 H, t, J=4.4), 4.09 (4 H, t, J=5.2), 6.61-6.63 (1 H,m), 7.54-7.57 (1 H, m), 8.78 (2 H, s), 9.03 (1 H, s), 9.20 (1 H, s),9.44-9.46 (1 H, m), 11.88 (1 H, s). MS: (ESI+): MH+=421

Example 2436-(((pyridin-3-yl)methoxy)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine319

Following the procedures for compound 314,(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol in DMFand sodium hydride was alkylated with 3-picolyl chloride to give4-(2-chloro-6-((pyridin-3-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine.Suzuki coupling of4-(2-chloro-6-((pyridin-3-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholineand 7 was carried out via General Procedure A. Purification using columnchromatography gave 319. NMR: CDCl₃: 3.90-3.94 (4 H, m, CH₂), 4.08-4.13(4 H, m, CH₂), 4.68 (2 H, s, CH₂), 4.88 (2 H, s, CH₂), 7.30 (1 H, dd, J7.79 and 4.87, Ar), 7.44 (1 H, s, Ar), 7.51 (1 H, t, J 8.14, Ar), 7.57(1 H, d, J 8.20, Ar), 7.71 (1 H, d, J 7.79, Ar), 8.28 (1 H, d, J 7.35,Ar), 8.58 (1 H, dd, J 4.80 and 1.47, Ar), 8.63 (1 H, d, J 1.86, Ar) and9.02 (1 H, s, Ar). MS: (ESI+): MH+ 459.16

Example 2446-(((pyridin-4-yl)methoxy)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine320

Following the procedures for compound 314,(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol in DMFand sodium hydride was alkylated with 4-picolyl chloride to give4-(2-chloro-6-((pyridin-4-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine.Suzuki coupling of4-(2-chloro-6-((pyridin-4-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholineand 7 was carried out via General Procedure A. Purification using columnchromatography gave 320. NMR: CDCl₃: 3.90-3.94 (4 H, m, CH₂), 4.08-4.13(4 H, m, CH₂), 4.68 (2 H, s, CH₂), 4.92 (2 H, s, CH₂), 7.30 (2 H, d, J5.81, Ar), 7.46 (1 H, s, Ar), 7.51 (1 H, t, J 8.14, Ar), 7.60 (1 H, d, J8.20, Ar), 8.28 (1 H, d, J 7.32, Ar), 8.61 (2 H, d, J 5.27, Ar), 9.01 (1H, s, Ar) and 10.14 (1 H, s, NH). MS: (ESI+): MH+ 459.17

Example 245N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-hydroxy-2-methylpropanamide321

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (4 g) was reacted withacetone following General Procedure D to give the corresponding tertiaryalcohol. 75 mg of this crude material was used in a palladium catalyzedcross coupling reaction following General Procedure A to give 69 mg of321 after reversed phase HPLC purification. MS (Q1) 395 (M)+

Example 2462-(2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol322

To a solution of(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (50 mg, 0.2 mmol) in DMF (1.5 mL) was addedO-(7-azabenzotriazol-1-yl)-(N,N,N′,N′-tetramethyluroniumhexafluorophosphate (134 mg, 0.4 mmol), N,N-diisopropylethylamine (190μL, 1.1 mmol), then 2-hydroxyisobutyric acid (53 mg, 0.5 mmol). Theresulting solution stirred 30 min at room temperature. Excesshydroxylamine hydrochloride was added then the reaction was quenchedwith saturated aqueous NaHCO₃. The aqueous layer was extracted withEtOAc. The combined organics were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was utilized in a Suzukicoupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide322 after reverse phase HPLC purification (2 mg). MS (Q1) 453 (M)+

Example 247N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-hydroxyacetamide323

To a solution of(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (50 mg, 0.2 mmol) in DMF (1.5 mL) was addedO-(7-azabenzotriazol-1-yl)-(N,N,N′,N′-tetramethyluroniumhexafluorophosphate (134 mg, 0.4 mmol), N,N-diisopropylethylamine (190μL, 1.1 mmol), then glycolic acid (38 mg, 0.5 mmol). The resultingsolution stirred 30 min at room temperature. Excess hydroxylaminehydrochloride was added then the reaction was quenched with saturatedaqueous NaHCO₃. The aqueous layer was extracted with EtOAc. The combinedorganics were dried over Na₂SO₄, filtered, and concentrated in vacuo.The crude product was utilized in a Suzuki coupling using GeneralProcedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 to provide323 after reverse phase HPLC purification (26 mg). MS (Q1) 425 (M)+

Example 2482-(2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol324

To a solution of(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (50 mg, 0.2 mmol) in DMF (1.5 mL) was addedO-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (134 mg, 0.4 mmol), N,N-diisopropylethylamine (190μL, 1.1 mmol), then 3-(methylsulfonyl)benzoic acid (102 mg, 0.5 mmol).The resulting solution stirred 30 min at room temperature. Excesshydroxylamine hydrochloride was added then the reaction was quenchedwith saturated aqueous NaHCO₃. The aqueous layer was extracted withEtOAc. The combined organics were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was utilized in a Suzukicoupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide324 after reverse phase HPLC purification (28 mg). MS (Q1) 549 (M)+

Example 2496-((1H-pyrazol-1-yl)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine325

To a solution of6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added pyrazole (18 mg, 0.3mmol) and K₂CO₃ (50 mg, 0.4 mmol). The resulting solution stirred atroom temperature overnight then was concentrated in vacuo. The residuewas diluted with water and filtered. The crude product was utilized in aSuzuki coupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide325 after reverse phase HPLC purification (13 mg). MS (Q1) 418 (M)+

Example 2501-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one326

To a solution of6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added2-hydroxybenzimidazole (35 mg, 0.3 mmol) and K₂CO₃ (50 mg, 0.4 mmol).The resulting solution stirred at room temperature overnight then wasconcentrated in vacuo. The residue was diluted with water and filtered.The crude product was utilized in a Suzuki coupling using GeneralProcedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide326 after reverse phase HPLC purification (3 mg). MS (Q1) 484 (M)+

Example 2513-(2-(1H-indazol-4-yl)-4-morpholinofuro[3,2-d]pyrimidin-6-yl)-N-methylsulfonylbenzenamine327

2-Chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine 45 from Example 27 wasreacted with 3-(methylsulfonylamino)phenylboronic acid via GeneralProcedure A to give the corresponding intermediate, after purificationby flash chromatography, which was then reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to give,after purification by reverse phase HPLC, 327. MS (Q1) 491 (M⁺)

Example 2522-(1H-indazol-4-yl)-6-(isoxazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine328

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (150 mg), 84 mgof 4-isoxazoleboronic acid pinacol ester and 14 mg ofbis(triphenylphosphine)palladium(II) dichloride in 0.7 mL of 1M Na₂CO₃aqueous solution and 0.7 mL of acetonitrile was heated to 100° C. in asealed microwave reactor for 10 min. The reaction mixture wasevaporated. The crude product was purified by flash chromatographyeluting with 0-20% MeOH/DCM to yield2-chloro-6-(isoxazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine (85 mg,67%).

2-Chloro-6-(isoxazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine (85 mg)was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 4.3 mg of 328. MS (Q1) 405.1 (M)⁺

Example 2533-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-ethylbenzamide329

3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (55 mg)was reacted with ethylamine via General Procedure B to yield3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-ethylbenamide.Crude3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-ethylbenamide (59mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 14.5 mg of 329. MS (Q1) 485.1 (M)⁺

Example 254N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-(N-methylsulfonylamino)acetamide330

To a solution of(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (150 mg, 0.5 mmol) in DMF (4.5 mL) was addedO-(7-azabenzotriazol-1-yl)-(N,N,N′,N′-tetramethyluroniumhexafluorophosphate (400 mg, 1 mmol), N,N-diisopropylethylamine (550 μL,3.2 mmol), then N-Boc glycine (270 mg, 1.5 mmol). The resulting solutionstirred 30 min at room temperature. Excess hydroxylamine hydrochloridewas added then the reaction was quenched with saturated aqueous NaHCO₃.The aqueous layer was extracted with EtOAc. The combined organics weredried over Na₂SO₄, filtered, and concentrated in vacuo. A portion of thecrude product (0.5 mmol) was dissolved in CH₂Cl₂ (15 mL), MeOH (15 mL),Et₂O (6 mL), and 4 M HCl in dioxane (6 mL) was added. The resultingmixture stirred at room temperature overnight. The reaction mixture wasconcentrated in vacuo. A portion of the crude material (0.3 mmol) wasdissolved in CH₂Cl₂ (8 mL) and Et₃N (4 mL) and methanesulfonyl chloride(450 μL, 6 mmol) was added. The reaction mixture stirred at roomtemperature overnight. The reaction was quenched by the addition ofwater then extracted with EtOAc. The combined organics were dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude material wasutilized in a Suzuki coupling according to General Procedure A using4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide330 after reverse phase HPLC purification (36 mg). MS (Q1) 502 (M)+

Example 255N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-aminoacetamide331

To a solution of(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (150 mg, 0.5 mmol) in DMF (4.5 mL) was addedO-(7-azabenzotriazol-1-yl)-(N,N,N′,N′-tetramethyluroniumhexafluorophosphate (400 mg, 1 mmol), N,N-diisopropylethylamine (550 μL,3.2 mmol), then N-Boc glycine (270 mg, 1.5 mmol). The resulting solutionstirred 30 min at room temperature. Excess hydroxylamine hydrochloridewas added then the reaction was quenched with saturated aqueous NaHCO₃.The aqueous layer was extracted with EtOAc. The combined organics weredried over Na₂SO₄, filtered, and concentrated in vacuo. A portion of thecrude product (0.5 mmol) was dissolved in CH₂Cl₂ (15 mL), MeOH (15 mL),Et₂O (6 mL), and 4 M HCl in dioxane (6 mL) was added. The resultingmixture stirred at room temperature overnight. The reaction mixture wasconcentrated in vacuo. A portion of the crude material (0.2 mmol) wasutilized in a Suzuki coupling according to General Procedure A using4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide331 after reverse phase HPLC purification (2 mg). MS (Q1) 424 (M)+

Example 2562-(1H-indazol-4-yl)-4-morpholino-6-(1-(4-N-methylsulfonylpiperazin-1-yl)ethyl)thieno[3,2-d]pyrimidine332

To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (500mg) in THF (20 mL) at −78° C. was added n-butyllithium (0.94 mL of a 2.5M solution in hexanes) and the reaction stirred at −78° C. for 1 h.Then, acetaldehyde (0.33 mL) was added and the reaction allowed to warmto room temperature over 16 h. The reaction was quenched with water (20mL) and extracted into dichloromethane (2×20 mL). The combined organicswere dried (MgSO₄) and reduced in vacuo to give1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethanol as acream solid.

To a solution of1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethanol (500mg) in dichloromethane (20 mL) at 0° C. was added triethylamine (0.28mL) and then methanesulphonyl chloride (0.14 mL) and the reactionstirred at room temperature for 16 h. The reaction was quenched withwater (20 mL) and extracted into dichloromethane (2×20 mL). The combinedorganic layers were washed with aqueous brine solution (2×20 mL), dried(MgSO₄) and reduced in vacuo to give methanesulfonic acid1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethyl ester asa yellow solid.

To a solution of methanesulfonic acid1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethyl ester(300 mg) in acetonitrile (20 mL) was added N-sulfonylpiperazine amide(239 mg) and potassium carbonate (548 mg) and the reaction heated atreflux for 16 h. After cooling to room temperature, the solvent wasreduced in vacuo and the residue redissolved in dichloromethane (20 mL)and washed with saturated aqueous sodium hydrogen carbonate solution(2×20 mL), aqueous brine solution (2×20 mL), dried (MgSO₄), reduced invacuo and purified by column chromatography to give2-chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidineas an off-white solid.

2-Chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidinewas reacted with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in generalprocedure A. Purification by column chromatography yielded 332. NMR:CDCl₃: 1.56 (3 H, d, J 7.1, Me), 2.62-2.80 (4 H, m, CH₂), 2.81 (3 H, s,Me), 3.26-3.31 (4 H, m, CH₂), 3.95-3.99 (4 H, m, CH₂), 4.02-4.11 (5 H,m), 7.45 (1 H, s, Ar), 7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar) and 9.03 (1 H, s, Ar). MS:(ESI+): MH+ 528.31

Example 2572-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methoxy)-N,N-dimethylacetamide333

To a suspension of2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (500mg) in methanol (20 mL) at 0° C. was added sodium borohydride (66 mg).The reaction was stirred for 2 h then quenched with 1:1 saturatedaqueous sodium hydrogencarbonate solution—water (20 mL). The mixture wasstirred for 10 min and then filtered, washed with water and air dried togive (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol asa white solid (489 mg).

To a solution of(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol (180mg) in THF (20 mL) was added sodium hydride (2 eq., 50 mg) and themixture stirred at room temperature for 1 h. Then 2-chloro-N,Ndimethylacetamide (2 eq., 0.13 ml) was added and the reaction stirred at refluxfor 16 h. After cooling to room temperature the reaction was quenchedwith water (20 mL) and extracted into ethyl acetate (2×20 mL). Thecombined organics were washed with aqueous brine solution (2×20 mL),dried (MgSO₄), reduced in vacuo and purified by column chromatography togive2-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethoxy)-N,N-dimethyl-acetamideas a yellow solid.

2-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethoxy)-N,N-dimethyl-acetamidewas reacted with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in generalprocedure A. Purification by column chromatography yielded 333. NMR:CDCl₃: 3.02 (6 H, s, Me), 3.96-3.99 (4 H, m, CH₂), 4.09-4.13 (4 H, m,CH₂), 4.31 (2 H, s, CH₂), 4.95 (2 H, s, CH₂), 7.45 (1 H, s, Ar), 7.50 (1H, apparent triplet, J 8.2, Ar), 7.61 (1 H, d, J 8.2, Ar), 8.28 (1 H, d,J 7.5, Ar), 9.03 (1 H, s, Ar) and 10.30 (1 H, s, NH). MS: (ESI+): MH+453.20

Example 2582-(1H-indazol-4-yl)-6-((E)-3-methoxyprop-1-enyl)-4-morpholinothieno[3,2-d]pyrimidine334

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (150 mg), 85 mgof(E)-2-(3-methoxy-1-propen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 14 mg of bis(triphenylphosphine)palladium(II) dichloride in 1 mL of1M Na₂CO₃ aqueous solution and 1 mL of acetonitrile was heated to 100°C. in a sealed microwave reactor for 10 min. The reaction mixture wasevaporated. The crude product was purified by flash chromatographyeluting with 5-50% EtOAc/hexane to yield2-chloro-6-((E)-3-methoxyprop-1-enyl)-4-morpholinothieno[3,2-d]pyrimidine(87 mg, 68%).2-Chloro-6-((E)-3-methoxyprop-1-enyl)-4-morpholinothieno[3,2-d]pyrimidine(40 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 29.1 mg of 334. MS (Q1) 408.1 (M)⁺

Example 2592-(1H-indazol-4-yl)-6-(3-methoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidine335

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (150 mg), 66 mgof 3-methoxyphenylboronic acid and 14 mg ofbis(triphenylphosphine)palladium(II) dichloride in 1 mL of 1M Na₂CO₃aqueous solution and 1 mL of acetonitrile was heated to 100° C. in asealed microwave reactor for 20 min. The reaction mixture wasevaporated. The crude product was purified by flash chromatographyeluting with 0-50% EtOAc/hexane to yield2-chloro-6-(3-methoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidine (94 mg,66%).

2-Chloro-6-(3-methoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidine (94 mg)was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 8.1 mg of 335. MS (Q1) 444.2 (M)⁺

Example 2603-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)benzamide336

3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (49 mg)was reacted with (S)-(+)-1-amino-2-propanol via General Procedure B toyield3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)benzamide.3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)benzamide(56 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 24.8 mg of 336. MS (Q1) 515.2 (M)⁺

Example 261(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)(morpholino)methanone337

3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (49 mg)was reacted with morpholine via General Procedure B to yield3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(morpholino)methanone.Crude3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(morpholino)methanone(58 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 23.7 mg of 337. MS (Q1) 527.2 (M)⁺

Example 2623-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoicacid 338

3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid wascoupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7(100 mg) via General Procedure A to yield 7.6 mg of 338. MS (Q1) 458.1(M)⁺

Example 263(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone339

3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg)was reacted with 1-methylpiperizine via General Procedure B to yield3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone.Crude3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone(71 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 22.4 mg of 339. MS (Q1) 540.1 (M)⁺

Example 2643-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-(dimethylamino)ethyl)benzamide340

3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg)was reacted with N,N-dimethylethlenediamine via General Procedure B toyield3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-dimethylamino)ethyl)benzamide.Crude3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-dimethylamino)ethyl)benzamide(73 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 16 mg of 340. MS (Q1) 528.0 (M)⁺

Example 265N-(3-(2-(1H-indazol-4-yl)-4-morpholinofuro[3,2-d]pyrimidin-6-yl)phenyl)acetamide341

2-Chloro-6-iodo-4-morpholinofuro[3,2-d]pyrimidine 45 from Example 27 wasreacted with 3-acetamidophenylboronic acid via General Procedure A togive the corresponding intermediate, after purification by flashchromatography, which was then reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to give,after purification by reverse phase HPLC, 341. MS (Q1) 455 (M⁺)

Example 2665-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)pyridine-3-carboxamide342

5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylicacid (40 mg) was reacted with (S)-(+)-1-amino-2-propanol via GeneralProcedure B to yield5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)pyridine-3-carboxamide.Crude5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)pyridine-3-carboxamide(46 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 7.6 mg of 342. MS (Q1) 516.5. (M)⁺.

Example 2675-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-(dimethylamino)ethyl)pyridine-3-carboxamide343

5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylicacid (40 mg) was reacted with N,N-dimethylethylenediamine via GeneralProcedure B to yield5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-dimethylamino)ethyl)pyridine-3-carboxamide.Crude5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-dimethylamino)ethyl)pyridine-3-carboxamide(46 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 22.3 mg of 343. MS (Q1) 529.0 (M)⁺

Example 2685-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylpyridine-3-carboxamide344

5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylicacid (40 mg) was reacted with methylamine hydrochloride via GeneralProcedure B to yield5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylpyridine-3-carboxamide.Crude5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylpyridine-3-carboxamide(41 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 10.6 mg of 344. MS (Q1) 472.0 (M)⁺

Example 2692-(2-(1H-indol-6-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol345

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (4 g) was reacted withacetone following General Procedure D to give the corresponding tertiaryalcohol. 75 mg of this crude material was used in a palladium catalyzedcross coupling reaction following General Procedure A to give 18 mg of345 after reversed phase HPLC purification. MS (Q1) 395 (M)+

Example 2702-(4-morpholino-2-(quinolin-3-yl)thieno[3,2-d]pyrimidin-6-yl)propan-2-ol346

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (2 g) was used along withacetone following General Procedure D to give the corresponding tertiaryalcohol. 75 mg of this crude material was used in a palladium catalyzedcross coupling reaction following General Procedure A to give 8 mg of346 after reversed phase HPLC purification. MS (Q1) 407 (M)+

Example 271(5-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridin-3-yl)(morpholino)methanone347

5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylicacid (40 mg) was reacted with morpholine via General Procedure B toyield5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-yl)(morpholine)methanone.Crude5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-yl)(morpholine)methanone(47 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 10.6 mg of 347 MS (Q1) 528.1 (M)⁺

Example 272(5-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridin-3-yl)(4-methylpiperazin-1-yl)methanone348

5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylicacid (40, mg) was reacted with 1-methylpiperizine via General ProcedureB to yield5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-yl)(4-methylpiperazin-1-yl)methanone.Crude5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-yl)(4-methylpiperazin-1-yl)methanone(48 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 14.6 mg of 348. MS (Q1) 541.1 (M)⁺

Example 2735-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylicacid 349

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19, 200 mg of3-ethoxycarbonylpyridine-5-boronic acid pinacol ester (250 mg) and 23 mgof bis(triphenylphosphine)palladium(II) dichloride in 1.5 mL of 1MNa₂CO₃ aqueous solution and 1.5 mL of acetonitrile was heated to 100° C.in a sealed microwave reactor for 10 min. The reaction mixture wasevaporated. The crude product was purified by flash chromatographyeluting with 10-100% EtOAc/hexane to yield ethyl5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylate(240 mg, 75%).

Ethyl5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylate(240 mg) and 27 mg of lithium hydroxide monohydrate were dissolved in 4mL of THF and 4 mL of H₂O. The reaction was stirred for 2 h at roomtemperature. The mixture was evaporated, and then added H₂O. The mixturewas acidified with 1N HCl to pH=2˜3. The resulting solid was filteredand washed with H₂O to yield5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylicacid (250 mg).

5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylicacid (40 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 5 mg of 349. MS (Q1) 459.1 (M)⁺

Example 274N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-(dimethylamino)acetamide350

To a solution of(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (50 mg, 0.2 mmol) in CH₂Cl₂ (4 mL) was added Et₃N (84 μL, 0.6mmol) and dimethylglycine ethyl ester (0.3 mmol). The reaction stirred18-48 h at room temperature before being quenched with water. Theaqueous layer was extracted with EtOAc. The combined organics were driedover Na₂SO₄ and concentrated in vacuo to giveN-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-(dimethylamino)acetamidewhich was utilized in a Suzuki coupling according to General ProcedureA. The crude material was purified by reversed phase HPLC to give 350(10 mg). MS (Q1) 452 (M)+

Example 2752-(4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[2,3-d]pyrimidin-6-yl)propan-2-ol351

2-(2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)propan-2-ol (100) mgwas reacted with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridinevia General Procedure A to give 120 mg of 351 following reverse phaseHPLC purification. MS (Q1) 396.2 (M)+

Example 276N-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-N-methylacetamide352

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19, 129 mg of3-acetamidophenylboronic acid (250 mg) and 23 mg ofbis(triphenylphosphine)palladium(II) dichloride in 1.5 mL of 1M Na₂CO₃aqueous solution and 1.5 mL of acetonitrile was heated to 100° C. in asealed microwave reactor for 15 min. Upon completion, the reactionmixture was evaporated. The crude product was purified by flashchromatography eluting with 20˜100% EtOAc/hexane to yieldN-(3-(2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)phenyl)acetamide(530 mg, 53%).

To a solution of 60 mg ofN-(3-(2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)phenyl)acetamideand 78 mg of cesium carbonate in DMF was added 12 μL of iodomethane. Thereaction mixture was stirred for 2 h at room temperature. The mixturewas diluted with ethyl acetate, washed with H₂O. The organic layer wasdried over (MgSO₄) and evaporated to yieldN-(3-(2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)phenyl)-N-methylacetamide.

N-(3-(2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)phenyl)-N-methylacetamide(62 mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A to yield 352. MS (Q1) 485.2 (M)⁺

Example 277(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(4-N-methylsulfonylpiperidin-4-yl)methanol353

Tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1 g) in 20 mL ofdichloromethane was combined with 2 g of Dess-Martin periodinane andstirred for 2 h, filtered through celite, extracted with saturatedsodium bicarbonate, and evaporated. The crude product was placed on acolumn and 325 mg of the aldehyde, tert-butyl4-formylpiperidine-1-carboxylate, was isolated. 260 mg2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 was reacted with 325 mgof tert-butyl 4-formylpiperidine-1-carboxylate following GeneralProcedure D to give 100 mg of tert-butyl4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(hydroxy)methyl)piperidine-1-carboxylate.The Boc group was removed from 100 mg of the alcohol using 0.125 mL of a4.0 M HCl solution in dioxane in 10 mL of DCM with 0.5 mL of methanol.After several hours the DCM, methanol, and HCl was evaporated. The crudeamine,(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(piperidin-4-yl)methanol,was mesylated in 3 mL of DCM and 0.04 mL of triethylamine with 0.03 mLof methanesulfonyl chloride. The 4-N-methylsulfonylpiperidinyl compoundwas then coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 followingGeneral Procedure A to give 70 mg of 353 after reversed phase HPLCpurification. MS (Q1) 530 (M)+

Example 2781-(2-(1H-indazol-4-yl)-4-morpholinofuro[3,2-d]pyrimidin-6-yl)ethanol354; and enantiomers:(S)-1-(2-(1H-indazol-4-yl)-4-morpholinofuro[3,2-d]pyrimidin-6-yl)ethanol294 and(R)-1-(2-(1H-indazol-4-yl)-4-morpholinofuro[3,2-d]pyrimidin-6-yl)ethanol295

A solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine 38 from Example19 (0.3 mmol) dissolved in THF (3 mL) at −78° C. was added 1.6M solutionof n-butyllithium (0.39 mmol). The reaction mixture was stirred for 30mins at which point acetaldehyde (1.2 mmol) was added. The reaction wasstirred for one hour and quenched with ice and allowed to warm to roomtemperature. The aqueous layer was extracted with methylene chloride andthe organic layer was filtered through sodium sulfate. The organic phasewas concentrated to yield1-(2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-yl)ethanol (72 mg).

1-(2-Chloro-4-morpholinofuro[3,2-d]pyrimidine-6-yl)ethanol (0.25 mmol)was dissolved in acetonitrile (1.5 mL) and treated with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole (0.62 mmol),PdCl2(PPh3)2 (0.025 mmol) and aqueous 1M potassium acetate (0.75 mmol).The vial was sealed and heated with stirring in a microwave to 150 degC. for 14 mins. The crude reaction mixture was filtered andconcentrated. The racemic product was purified by reverse phasechromatography to give racemic 354. Chiral chromatography of racemic 354separated the two enantiomers 294- and 295.

Example 2792-(1H-indazol-4-yl)-4-morpholino-6-((pyridin-3-yloxy)methyl)thieno[3,2-d]pyrimidine355

To a suspension of2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (900mg) in toluene (20 mL) at 40° C. was added phosphorus tribromide (0.10mL) and the reaction mixture was heated at 100° C. for 16 h. Aftercooling to room temperature, the reaction was diluted withdichloromethane (40 mL) and washed with saturated aqueous sodiumhydrogen carbonate solution (2×40 mL). The organic layer was dried(MgSO₄) and reduced in vacuo to give6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as ayellow solid.

To a solution of 3-hydroxypyridine (102 mg) in THF (10 mL) was addedsodium hydride (43 mg) and the reaction stirred at room temperature for1 h. Then,6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (150 mg)was added and the reaction stirred at room temperature for 16 h. Thereaction was quenched with water (20 mL) and extracted into ethylacetate (2×20 mL). The combined organics were washed with aqueous brinesolution (2×20 mL), dried (MgSO₄), reduced in vacuo and purified bycolumn chromatography to give2-chloro-4-morpholin-4-yl-6-phenoxymethyl-thieno[3,2-d]pyrimidine as awhite solid.

2-Chloro-4-morpholin-4-yl-6-phenoxymethyl-thieno[3,2-d]pyrimidine wasreacted with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in generalprocedure A. Purification by column chromatography yielded 355. NMR:CDCl₃: 3.81-3.84 (4 H, m, CH₂), 4.02-4.05 (4 H, m, CH₂), 5.41 (2 H, s,CH₂), 7.12-7.15 (1 H, m, Ar), 7.21-7.23 (1 H, m, Ar), 7.42-7.43 (1 H, m,Ar), 7.45 (1 H, s, Ar), 7.50 (1 H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5,Ar), 8.40-8.42 (1 H, m, Ar) and 9.03 (1 H, s, Ar). MS: (ESI+): MH+445.18

Example 2807-methyl-6-(5-(methylsulfonyl)pyridin-3-yl)-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidine356

2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine (150 mg)was coupled to 3-methanesulphonylamino methyl benzeneboronic acid, andthen reacted with 7-azaindole-5-boronic acid pinacol ester via GeneralProcedure F. The product was purified by reverse phase HPLC to yield 79mg of 356. MS. (Q1) 507.1 (M)⁺

Example 2816-((hexahydro-2-methylsulfonylpyrrolo[3,4-c]pyrrol-5(1H)-yl)methyl)-2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine357

To intermediate2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 10 fromExample 3 (100 mg, 0.35 mmol) in 1,2-dichloroethane (2 mL) was addedacetic acid (20 μL, 0.35 mmol), and2-BOC-Hexahydro-pyrrolo[3,4-c]pyrrole (98 mg, 0.5 mmol) then Na(OAc)₃BH(90 mg, 0.42 mmol). The reaction stirred overnight at room temperature.The reaction was quenched with water and extracted with DCM. Thecombined organics were dried over Na₂SO₄, filtered, and concentrated invacuo. The crude product was dissolved in CH₂Cl₂ (10 mL), MeOH (10 mL),Et₂O (2 mL), and 4 M HCl in dioxane (7 mL) was added. The resultingmixture stirred at room temperature overnight. The reaction mixture wasconcentrated in vacuo. The crude material was dissolved in CH₂Cl₂ (5 mL)and Et₃N (4 mL) and methanesulfonyl chloride (54 μL, 0.7 mmol) wereadded. The reaction mixture stirred at room temperature overnight. Thereaction was quenched by the addition of water then extracted withEtOAc. The combined organics were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude material was utilized in a Suzukicoupling according to General Procedure A using4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide357 after reverse phase HPLC purification (21 mg). MS (Q1) 540 (M)+

Example 2823-(2-(1H-indazol-4-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylbenzamide358

2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine fromExample 12 (0.1 g, 0.3 mmol), 3-(N-Methylaminocarbonyl)benzeneboronicacid (50 mg, 0.3 mmol), and bis(triphenylphosphine)palladium(II)dichloride (9 mg, 13 μmol) in 1 M aqueous Na₂CO₃ (0.5 mL) andacetonitrile (0.5 mL) were heated to 100° C. in a sealed microwavereactor for 10 min. Upon completion,4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (122 mg,0.5 mmol), bis(triphenylphosphine)palladium(II) dichloride (9 mg, 13μmol), 1 M aqueous Na₂CO₃ (1 mL), and acetonitrile (1 mL) were addedinto the same pot. The reaction mixture was heated to 150° C. in asealed microwave reactor for 20 min. The mixture was extracted withEtOAc and CH₂Cl₂. The combined organics were concentrated to yield 358after reverse phase HPLC purification (2 mg). MS (Q1) 485 (M)+

Example 283N-(3-(2-(1H-indazol-4-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)acetamide359

2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine fromExample 12 (0.1 g, 0.3 mmol), 3-Acetamidobenzeneboronic acid (50 mg, 0.3mmol), and bis(triphenylphosphine)palladium(II) dichloride (9 mg, 13μmol) in 1 M aqueous Na₂CO₃ (0.5 mL) and acetonitrile (0.5 mL) wereheated to 100° C. in a sealed microwave reactor for 10 min. Uponcompletion, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole7 (122 mg, 0.5 mmol), bis(triphenylphosphine)palladium(II) dichloride (9mg, 13 μmol), 1 M aqueous Na₂CO₃ (1 mL), and acetonitrile (1 mL) wereadded into the same pot. The reaction mixture was heated to 150° C. in asealed microwave reactor for 20 min. The mixture was extracted withEtOAc and CH₂Cl₂. The combined organics were concentrated to yield 359after reverse phase HPLC purification (10 mg). MS (Q1) 485 (M)+

Example 2842-(1H-indazol-4-yl)-7-methyl-6-(3-(methylsulfonyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidine360

2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine fromExample 12 (0.6 g, 1.5 mmol), 3-(methylsulfonyl)phenylboronic acid (0.3g, 1.5 mmol), and bis(triphenylphosphine)palladium(II) dichloride (53mg, 80 μmol) in 1 M aqueous Na₂CO₃ (3 mL) and acetonitrile (3 mL) wereheated to 100° C. in a sealed microwave reactor for 10 min. Uponcompletion the organic layer was separated and the aqueous layer wasextracted with EtOAc. The combined organics were concentrated in vacuo.A portion of the residue (0.38 mmol) was dissolved in 1 M Na₂CO₃ (1.5mL) and CH₃CN (1.5 mL) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 (0.2 g, 0.8mmol) and bis(triphenylphosphine)palladium(II) dichloride (13 mg, 20μmol) were added into the same pot. The reaction mixture was heated to150° C. in a sealed microwave reactor for 30 min. The mixture wasextracted with EtOAc and CH₂Cl₂. The combined organics were concentratedto yield 360 after reverse phase HPLC purification (90 mg). MS (Q1) 506(M)+

Example 2852-(1H-indazol-4-yl)-6-(4-methoxypyridin-3-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidine361

2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine fromExample 12 (0.1 g, 0.3 mmol), 4-Methoxy-3-pyridineboronic acid (42 mg,0.3 mmol), and bis(triphenylphosphine)palladium(II) dichloride (9 mg, 13μmol) in 1 M aqueous Na₂CO₃ (0.5 mL) and acetonitrile (0.5 mL) wereheated to 100° C. in a sealed microwave reactor for 10 min. Uponcompletion, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole7 (122 mg, 0.5 mmol), bis(triphenylphosphine)palladium(II) dichloride (9mg, 13 μmol), 1 M aqueous Na₂CO₃ (1 mL), and acetonitrile (1 mL) wereadded into the same pot. The reaction mixture was heated to 150° C. in asealed microwave reactor for 20 min. The mixture was extracted withEtOAc and CH₂Cl₂. The combined organics were concentrated to yield 361after reverse phase HPLC purification (28 mg). MS (Q1) 459 (M)+

Example 286N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3-methoxybenzamide362

(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (50.0 mg, 0.17 mM) was dissolved in 1.5 mL DMF. To this wasadded 77.6 mg (3.0 eq) of p-anisic acid, 129.3 mg (2.0 eq) HATU and 0.18uL (6.0 eq) DIPEA and the reaction heated at 40° C. for 18 hours.Complete reaction was confirmed by HPLC and 2.0 eq NH₂OH—H₂O was addedto the cooled reaction and the reaction stirred for ten minutes. Thereaction was diluted with Sat. NaHCO₃, extracted with EtOAc, washed withbrine, dried over MgSO₄ and concentrated in vacuo. This intermediate waspurified by flash chromatography (EtOAc/Hexanes) followed by Suzukicoupling of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7as per General Procedure A. Complete reaction was confirmed by LCMS andthe reaction was concentrated in vacuo to give 18.9 mg of the finalproduct after RP-HPLC purification (38% yield). MS (Q1) 501.3 (M)+

Example 287N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-methoxybenzamide363

(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (50.0 mg, 0.17 mM) was dissolved in 1.5 mL DMF. To this wasadded 77.6 mg (3.0 eq) of p-anisic acid, 129.3 mg (2.0 eq) HATU and 0.18uL (6.0 eq) DIPEA and the reaction heated at 40° C. for 18 hours.Complete reaction was confirmed by HPLC and 2.0 eq NH₂OH—H₂O was addedto the cooled reaction and the reaction stirred for ten minutes. Thereaction was diluted with sat. NaHCO₃, extracted with EtOAc, washed withbrine, dried over MgSO₄ and concentrated in vacuo. This intermediate waspurified by flash chromatography (EtOAc/Hexanes) followed by Suzukicoupling of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7as per General Procedure A. Complete reaction was confirmed by LCMS andthe reaction was concentrated in vacuo to give 18.9 mg of 363 afterRP-HPLC purification (38% yield). MS (Q1) 501.3 (M)+

Example 288N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-methoxybenzenamine364

To a 20 mL vial containing6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (54.8 mg, 0.16 mM) dissolved in 3 mL DMF was added 19.7 mg(1.0 eq) p-Anisidine and 30.4 mg (1.4 eq) K₂CO₃. The vial was capped andthe reaction was stirred overnight at RT. Complete reaction wasconfirmed by LCMS and the resulting intermediate was purified by flashchromatography to give 42.6 mg of product (68% yield). This intermediatewas reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure A. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 24.7 mg of 364 after RP-HPLCpurification (47% yield). MS (Q1) 473.3 (M)+

Example 2892-(1H-indazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine365

To a 20 mL vial containing6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (54.8 mg, 0.16 mM) dissolved in 3 mL DMF was added 13.14 mg(1.0 eq) 2-methylimidazole and 30.4 mg (1.4 eq) K₂CO₃. The vial wascapped and the reaction was stirred overnight at RT. Complete reactionwas confirmed by LCMS and the resulting intermediate was purified byflash chromatography to give 40 mg of product (71% yield). Thisintermediate was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure A. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 24.3 mg of 365 after RP-HPLCpurification (51% yield). MS (Q1) 432.2 (M)+

Example 290N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-methoxybenzenamine366

To a 20 mL vial containing6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (54.8 mg, 0.16 mM) dissolved in 3 mL DMF was added 19.7 mg(1.0 eq) o-anisidine and 30.4 mg (1.4 eq) K₂CO₃. The vial was capped andthe reaction was stirred overnight at RT. Complete reaction wasconfirmed by LCMS and the resulting intermediate was purified by flashchromatography to give 40 mg of product (64% yield). This intermediatewas reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure A. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 23.0 mg of 366 after RP-HPLCpurification (49% yield). MS (Q1) 473.3 (M)+

Example 2913-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-methylbenzamide367

To a 20 mL vial containing6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (54.8 mg, 0.16 mM) dissolved in 3 mL DMF was added 24.0 mg(1.0 eq) 3-Aminobenzoylmethylamide and 30.4 mg (1.4 eq) K₂CO₃. The vialwas capped and the reaction was stirred overnight at RT. Completereaction was confirmed by LCMS and the resulting intermediate waspurified by flash chromatography to give 50.1 mg of product (75% yield).This intermediate was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure A. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 33.3 mg of 367 after RP-HPLCpurification (56% yield). MS (Q1) 500.3 (M)+

Example 292N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-6-methoxypyridin-3-amine368

To a 20 mL vial containing6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (54.8 mg, 0.16 mM) dissolved in 3 mL DMF was added 19.9 mg(1.0 eq) of 5-amino-2-methoxypyridine and 30.4 mg (1.4 eq) K₂CO₃. Thevial was capped and the reaction was stirred overnight at RT. Completereaction was confirmed by LCMS and the resulting intermediate waspurified by flash chromatography to give 56.0 mg of product (89% yield).This intermediate was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure A. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 8.8 mg of 368 after RP-HPLCpurification (12% yield). MS (Q1) 474.2 (M)+

Example 293N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)pyridin-3-amine369

To a 20 mL vial containing6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (54.8 mg, 0.16 mM) dissolved in 3 mL DMF was added 15.06 mg(1.0 eq) of 3-aminopyridine and 30.4 mg (1.4 eq) K₂CO₃. The vial wascapped and the reaction was stirred overnight at RT. Complete reactionwas confirmed by LCMS and the resulting intermediate was purified byflash chromatography to give 55.0 mg of product (95% yield). Thisintermediate was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure A. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 1.5 mg of 369 after RP-HPLCpurification (2% yield). MS (Q1) 444.2 (M)+

Example 294N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-morpholinobenzenamine370

To a 20 mL vial containing6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (54.8 mg, 0.16 mM) dissolved in 3 mL DMF was added 28.5 mg(1.0 eq) of 4-morpholinoaniline and 30.4 mg (1.4 eq) K₂CO₃. The vial wascapped and the reaction was stirred overnight at RT. Complete reactionwas confirmed by LCMS and the resulting intermediate was purified byflash chromatography to give 60.0 mg of product (84% yield). Thisintermediate was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure A. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 11.2 mg of 370 after RP-HPLCpurification (16% yield). MS (Q1) 528.3 (M)+

Example 295N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1H-pyrazol-5-amine371

To a 20 mL vial containing6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (54.8 mg, 0.16 mM) dissolved in 3 mL DMF was added 13.3 mg(1.0 eq) of 3-aminopyrazole and 30.4 mg (1.4 eq) K₂CO₃. The vial wascapped and the reaction was stirred overnight at RT. Complete reactionwas confirmed by LCMS and the resulting intermediate was purified byflash chromatography to give 46 mg of product (82% yield). Thisintermediate was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure A. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 15.3 mg of 371 after RP-HPLCpurification (27% yield). MS (Q1) 433.2 (M)+

Example 296N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1,3-dihydrobenzo[c]thiophen-1,1-dioxide-5-amine372

To a 20 mL vial containing6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (54.8 mg, 0.16 mM) dissolved in 3 mL DMF was added 29.3 mg(1.0 eq) of 5-amino-2,3-dihydro-1H-2lambda-6-benzo[c]thiophene-2,2-dione and 30.4 mg (1.4 eq) K₂CO₃. Thevial was capped and the reaction was stirred overnight at RT. Completereaction was confirmed by LCMS and the resulting intermediate waspurified by flash chromatography to give 57.5 mg of product (80% yield).This intermediate was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure A. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 17.4 mg of 372 after RP-HPLCpurification (25% yield). MS (Q1) 533.2 (M)+

Example 297N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-6-morpholinopyridin-3-amine373

To a 20 mL vial containing6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (54.8 mg, 0.16 mM) dissolved in 3 mL DMF was added 28.7 mg(1.0 eq) of 3-amino-6-morpholino-pyridine and 30.4 mg (1.4 eq) K₂CO₃.The vial was capped and the reaction was stirred overnight at RT.Complete reaction was confirmed by LCMS and the resulting intermediatewas purified by flash chromatography to give 58.0 mg of product (81%yield). This intermediate was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure A. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 34.8 mg of 373 after RP-HPLCpurification (51% yield). MS (Q1) 529.3 (M)+

Example 298N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3-methylsulfonylaminobenzene-1-amine374

To a 20 mL vial containing6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (54.8 mg, 0.16 mM) dissolved in 3 mL DMF was added 29.8 mg(1.0 eq) of N-(3-aminophenyl)methane sulfonamide and 30.4 mg (1.4 eq)K₂CO₃. The vial was capped and the reaction was stirred overnight at RT.Complete reaction was confirmed by LCMS and the resulting intermediatewas purified by flash chromatography to give 20 mg of product (28%yield). This intermediate was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure A. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 14.3 mg of 374 after RP-HPLCpurification (53% yield). MS (Q1) 536.2 (M)+

Example 299N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3-(methylsulfonyl)benzenamine375

To a 20 mL vial containing6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 fromExample 9 (54.8 mg, 0.16 mM) dissolved in 3 mL DMF was added 24.5 mg(1.0 eq) of 3-(methylsulfonyl)aniline and 30.4 mg (1.4 eq) K₂CO₃. Thevial was capped and the reaction was stirred overnight at RT. Completereaction was confirmed by LCMS and the resulting intermediate waspurified by flash chromatography to give 25.6 mg of product (36% yield).This intermediate was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure A. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 11.8 mg of 375 after RP-HPLCpurification (38% yield). MS (Q1) 521.2 (M)+

Example 300(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-cyclopropylsulfonylmethanamine376

(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (53.2 mg, 0.19 mM) was reacted with cyclopropanesulfonylchloride (2.2 eq) followed by Suzuki coupling of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as pergeneral procedure K. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 16.7 mg of 376 after RP-HPLCpurification (40% yield). MS (Q1) 471.3 (M)+

Example 301N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-(3-methoxyphenyl)acetamide377

(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (53.2 mg, 0.19 mM) was reacted with 3-methoxyphenylacetylchloride (2.2 eq) followed by Suzuki coupling of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure K. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 16.0 mg of 377 after RP-HPLCpurification (33% yield). MS (Q1) 515.3 (M)+

Example 302N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-(4-methoxyphenyl)acetamide378

(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (53.2 mg, 0.19 mM) was reacted with 4-methoxyphenylacetylchloride (2.2 eq) followed by Suzuki coupling of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure K. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 18.8 mg of 378 after RP-HPLCpurification (42% yield). MS (Q1) 515.3 (M)+

Example 303(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylsulfonylmethanamine379

(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (53.2 mg, 0.19 mM) was reacted with isopropylsulfonylchloride (2.2 eq) followed by Suzuki coupling of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure K. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 2.8 mg of 379 after RP-HPLCpurification (17% yield). MS (Q1) 473.2 (M)+

Example 3042-(N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-bis-(N-cyclopropylacetamide)-methanamine380

To (2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (110 mg, 0.39 mM) in 5 mL DMF was added 48.2 uL (1.06 eq)2,6-lutidine and N1-cyclopropyl-2-chloroacetamide (1.2 eq) followed bySuzuki coupling of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure K. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 10.0 mg of 380 after RP-HPLCpurification (22% yield). MS (Q1) 561.3 (M)+

Example 3051-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-methylsulfonylazetidin-3-amine381

To 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 10 fromExample 3 (100 mg, 0.35 mmol) in 1,2-dichloroethane (2 mL) was addedacetic acid (20 μL, 0.35 mmol), and 3-N-BOC-aminoazetidine (78 mg, 0.5mmol) then Na(OAc)₃BH (90 mg, 0.42 mmol). The reaction stirred overnightat room temperature then was quenched with water and extracted with DCM.The combined organics were dried over Na₂SO₄, filtered, and concentratedin vacuo. The crude product was dissolved in CH₂Cl₂ (10 mL), MeOH (10mL), and 4 M HCl in dioxane (10 mL) was added. The resulting mixturestirred at room temperature for 1 h then was concentrated in vacuo. Thecrude material was dissolved in CH₂Cl₂ (5 mL) and Et₃N (4 mL) andmethanesulfonyl chloride (110 μL, 1.4 mmol) was added. The reactionmixture stirred at room temperature overnight then was quenched by theaddition of water and extracted with EtOAc. The combined organics weredried over Na₂SO₄, filtered, and concentrated in vacuo to giveN-(1-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)methanesulfonamidewhich was utilized in a Suzuki coupling according to General Procedure Ausing 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 toprovide 381 after reverse phase HPLC purification (2 mg). MS (Q1) 500(M)+

Example 3062-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methylamino)-N-cyclopropylacetamide382

To (2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 fromExample 11 (110 mg, 0.39 mM) in 5 mL DMF was added 48.2 uL (1.06 eq)2,6-lutidine and N1-cyclopropyl-2-chloroacetamide (1.2 eq) followed bySuzuki coupling of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure K. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 6.5 mg of 382 after RP-HPLCpurification (40% yield). MS (Q1) 464.3 (M)+

Example 307N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-(methylsulfonyl)ethanamine383

To a mixture of N-(2-bromoethyl)phthalimide (500 mg) in DMSO (8 mL) wasadded sodium thiomethoxide (152 mg) and the reaction stirred at roomtemperature for 16 h. Then with water (2 mL) was added and the mixturestirred at room temperature for 10 min. The reaction was diluted withwater (20 mL) and extracted into ethyl acetate (2×20 mL). The combinedorganics were washed with aqueous brine solution (2×20 mL), dried(MgSO₄) and reduced in vacuo to give2-(2-methylsulfanyl-ethyl)-isoindole-1,3-dione as a white solid.

To a solution of 2-(2-methylsulfanyl-ethyl)-isoindole-1,3-dione (400 mg)in methanol (10 mL) was added a solution of oxone (1.67 g) in water (10mL) and the reaction stirred at room temperature for 16 h. The reactionwas then diluted with water (20 mL) and extracted into dichloromethane(2×20 mL). The combined organics were washed with aqueous brine solution(2×20 mL), dried (MgSO₄) and reduced in vacuo to give2-(2-methanesulfonyl-ethyl)-isoindole-1,3-dione as a white solid.

To a solution of 2-(2-methanesulfonyl-ethyl)-isoindole-1,3-dione (387mg) in ethanol (10 mL) was added hydrazine monohydrate (0.60 mL) and thereaction was heated at reflux for 3 h. After cooling to roomtemperature, the mixture was filtered and the filtrate reduced in vacuoto give 2-methanesulfonyl-ethylamine as a white solid.

To a solution of2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (277mg) in methanol (10 mL) was added 2-methanesulfonyl-ethylamine (234 mg)and the reaction stirred at room temperature for 16 h. The solvent wasreduced in vacuo and the residue redissolved in ethanol (50 mL).Palladium on carbon (20 mg) was added and the reaction stirred at roomtemperature under a hydrogen balloon for 48 h. The reaction was thenfiltered through Celite and the filtrate reduced in vacuo to give(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(2-methanesulfonyl-ethyl)-amineas a white solid.

(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(2-methanesulfonyl-ethyl)-aminewas reacted with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in GeneralProcedure A. Purification by column chromatography yielded 383. NMR:CDCl₃: 2.95 (3 H, s, Me), 3.18-3.21 (4 H, m, CH₂), 3.82-3.85 (4 H, m,CH₂), 4.01-4.04 (4 H, m, CH₂), 4.12 (2 H, s, CH₂), 7.45 (1 H, s, Ar),7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1 H, d, J 8.2, Ar), 8.28(1 H, d, J 7.5, Ar) and 9.03 (1 H, s, Ar). MS: (ESI+): MH+ 473.22

Example 308N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3-(methylsulfonyl)propan-1-amine384

To a mixture of N-(3-bromopropyl)phthalimide (500 mg) in DMSO (8 mL) wasadded sodium thiomethoxide (144 mg) and the reaction stirred at roomtemperature for 16 h. Then with water (2 mL) was added and the mixturestirred at room temperature for 10 min. The reaction was diluted withwater (20 mL) and extracted into ethyl acetate (2×20 mL). The combinedorganics were washed with aqueous brine solution (2×20 mL), dried(MgSO₄) and reduced in vacuo to give2-(3-methylsulfanyl-propyl)-isoindole-1,3-dione as a white solid.

To a solution of 2-(3-methylsulfanyl-propyl)-isoindole-1,3-dione (440mg) in methanol (10 mL) was added a solution of oxone (1.73 g) in water(10 mL) and the reaction stirred at room temperature for 16 h. Thereaction was then diluted with water (20 mL) and extracted intodichloromethane (2×20 mL). The combined organics were washed withaqueous brine solution (2×20 mL), dried (MgSO₄) and reduced in vacuo togive 2-(3-methanesulfonyl-propyl)-isoindole-1,3-dione as a white solid.

To a solution of 2-(3-methanesulfonyl-propyl)-isoindole-1,3-dione (407mg) in ethanol (10 mL) was added hydrazine monohydrate (0.80 mL) and thereaction was heated at reflux for 3 h. After cooling to roomtemperature, the mixture was filtered and the filtrate reduced in vacuoto give 3-methanesulfonyl-propylamine as a white solid.

To a solution of6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (200 mg)in acetonitrile (10 mL) was added 3-methanesulfonyl-propylamine (86 mg)and potassium carbonate (317 mg) and the reaction heated at 80° C. for16 h. After cooling to room temperature, the solvent was reduced invacuo and the residue redissolved in dicholoromethane (20 mL). Thesolution was washed with saturated aqueous sodium hydrogen carbonatesolution (20 mL), aqueous brine solution (2×20 mL), dried (MgSO₄),reduced in vacuo and purified by column chromatography to give(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(3-methanesulfonyl-propyl)-amineas a yellow solid.

(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(3-methanesulfonyl-propyl)-aminewas reacted with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in generalprocedure A. Purification by column chromatography yielded 384. NMR:CDCl₃: 1.99-2.05 (2 H, m, CH₂), 2.80 (2 H, t, J 7.2, CH₂), 2.81 (3 H, s,Me), 3.10-3.13 (2 H, m, CH₂), 3.85-3.88 (4 H, m, CH₂), 4.01-4.06 (6 H,m), 7.45 (1 H, s, Ar), 7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar) and 9.03 (1H, s, Ar). MS:(ESI+): MH+ 487.20

Example 309N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3-(dimethylaminosulfonyl)propan-1-amine385

To a suspension of dimethylamine hydrochloride (1.38 g) indichloromethane (20 mL) was added triethylamine (2.52 mL) and then3-chloropropanesulfonyl chloride (0.69 mL) and the reaction was stirredat room temperature for 16 h. The reaction was quenched with water (20mL) and extracted into dichloromethane (2×30 mL). The combined organicswere washed with 1 M aqueous hydrochloric acid solution (40 mL) thensaturated aqueous sodium hydrogen carbonate solution, dried (MgSO₄) andreduced in vacuo to give 3-chloro-propane-1-sulfonic acid dimethylamideas a yellow solid.

A mixture of 3-chloro-propane-1-sulfonic acid dimethylamide (1.06 g) andsodium iodide (2.57 g) in 2-butanone (20 mL) was heated at 80° C. for 16h. After cooling to room temperature the solvent was reduced in vacuo.The residue was partitioned between ethyl acetate (20 mL) and water (20mL). The organic layer was dried (MgSO₄) and reduced in vacuo to give3-iodo-propane-1-sulfonic acid dimethylamide as a yellow solid.

To a solution of 3-iodo-propane-1-sulfonic acid dimethylamide (600 mg)in DMF (10 mL) was added potassium phthalimide (590 mg) and the reactionheated at 100° C. for 16 h. After cooling to room temperature, thereaction was partitioned between dichloromethane (30 mL) and water (30mL). The organic layer was washed with aqueous brine solution (3×30 mL),dried (MgSO₄) and reduced in vacuo to give3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propane-1-sulfonic aciddimethylamide as a white solid.

To a solution of3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propane-1-sulfonic aciddimethylamide (530 mg) in ethanol (10 mL) was added hydrazinemonohydrate (0.80 mL) and the reaction was heated at reflux for 3 h.After cooling to room temperature, the mixture was filtered and thefiltrate reduced in vacuo to give 3-amino-propane-1-sulfonic aciddimethylamide as a white solid.

To a solution of2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (280mg) in methanol (10 mL) was added 3-amino-propane-1-sulfonic aciddimethylamide (284 mg) and the reaction stirred at room temperature for16 h. The solvent was reduced in vacuo and the residue redissolved inethanol (50 mL). Palladium on carbon (20 mg) was added and the reactionstirred at room temperature under a hydrogen balloon for 48 h. Thereaction was then filtered through Celite and the filtrate reduced invacuo to give3-[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-amino]-propane-1-sulfonicacid dimethylamide as a yellow solid.

3-[(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-amino]-propane-1-sulfonicacid dimethylamide was reacted with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in generalprocedure A. Purification by column chromatography yielded 385. NMR:CDCl₃: 1.99-2.01 (2 H, m, CH₂), 2.78-2.81 (2 H, m, CH₂), 2.82 (6 H, s,Me), 2.98-3.01 (2 H, m, CH₂), 3.84-3.88 (4 H, m, CH₂), 4.02-4.05 (4 H,m, CH₂), 4.07 (2 H, s, CH₂), 7.45 (1 H, s, Ar), 7.50 (1 H, apparenttriplet, J 8.2, Ar), 7.61 (1H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar)and 9.03 (1 H, s, Ar). MS: (ESI+): MH+ 516.34

Example 310N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-methyl(phenyl)methanamine386

2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 fromExample 3 (101 mg) was dissolved in 1,2-DCE and 1 eq AcOH and a smallscoop of molecular sieves (4 A) was added. To this 57 mg (1.3 eq) ofN-benzylmethylamine was added. The reaction was stirred for 25 minutesand 0.5 mL MeOH added. This was stirred an additional 5 minutes beforeadding 91.1 mg Na(OAc)₃BH and allowed to stir at room temperature 48hours. Complete reaction was confirmed by LCMS. Reaction was filteredand concentrated in vacuo and purified by flash chromatography to give58.6 mg of the intermediate (42% yield) followed by Suzuki coupling of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure A. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 12.9 mg of 386 after RP-HPLCpurification (18% yield). MS (Q1) 471.3 (M)+.

Example 311N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(3-methoxyphenyl)-N-methylmethanamine387

2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 fromExample 3 (101 mg) was dissolved in 1,2-DCE and 1 eq AcOH and a smallscoop of molecular sieves (4 A) was added. To this 71.1 mg (1.3 eq) of3-Methoxy-N-methylbenzylamine was added. The reaction was stirred for 25minutes and 0.5 ml MeOH added. This was stirred an additional 5 minutesbefore adding 91.1 mg Na(OAc)₃BH and allowed to stir at room temperature48 hours. Complete reaction was confirmed by LCMS. Reaction was filteredand concentrated in vacuo and purified by flash chromatography to give54.6 mg of the intermediate (36% yield) followed by suzuki coupling of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure A. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 31.5 mg of 387 after RP-HPLCpurification (42% yield). MS (Q1) 501z.3 (M)+

Example 312N-(2-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-yl)benzamide388

To a mixture of4-morpholino-2-(pyridine-3-yl)thieno[3,2-d]pyrimidine-6-carboxylic acid(610 mg, 2.04 mmol), 1-hydroxy-7-azabenzotriazole (56 mg, 0.4 mmol),O-(7-azabenzotriazol-1-yl)-(N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU; 1.2 g, 3.1 mmol), andN,N-diisopropylethylamine (1.4 mL, 8.1 mmol) in DMF (3 mL) was addedammonium chloride (330 mg, 6.1 mmol). The reaction mixture was stirredovernight at room temperature. The mixture was diluted with EtOAc,washed with saturated aqueous NaHCO₃ and brine. The aqueous layer wasextracted with EtOAc. The combined organics were washed with saturatedNaHCO₃ and brine then dried over MgSO₄, filtered and concentrated invacuo. The residue was purified by silica gel chromatography (0-20% MeOHin CH₂Cl₂) to afford2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide (490 mg, 81%yield).

Zirconium (IV) chloride (780 mg, 3.3 mmol) was added to a mixture of2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carboxamide (400 mg, 1.3mmol) in THF (8 mL) at −10° C. The reaction mixture was stirred for 1 hat −10° C. A solution of methylmagnesium bromide (2.7 mL, 3 M in Et₂O)was added dropwise. The resulting mixture was warmed to room temperatureand stirred overnight. The reaction was quenched by the addition ofwater. The organic layer was separated and the aqueous layer wasextracted with EtOAc. The aqueous solution was then basified withsaturated NaHCO₃ and again extracted with EtOAc. The combined organiclayers were dried over MgSO₄, filtered, and concentrated in vacuo. Thecrude mixture was purified by silica gel chromatography (0-15% MeOH inCH₂Cl₂) to afford2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-amine (220mg, 53% yield).

To a solution of2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-amine (1.1g, 3.5 mmol) in CH₂Cl₂ (50 mL) was added Et₃N (0.6 mL, 4.9 mmol) andbenzoyl chloride (0.6 mL, 4.2 mmol). The resulting mixture stirred atroom temperature overnight. The reaction was diluted with 1 M HCl andextracted with DCM, dried over MgSO₄, and concentrated in vacuo. Thecrude material was purified by silica gel chromatography (0-50% EtOAc inhexane). A portion (0.65 mmol) of the crude material was utilized in aSuzuki coupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide388 after reverse phase HPLC purification (133 mg). MS (Q1) 499 (M)+

Example 313(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine389

1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine55 from Example 11a was reacted with 0.18 g (1.3 eq) of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure A to give 18 mg of 389 after RP-HPLC purification (28%yield). MS (Q1) 381.2 (M)+

Example 314N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-methylbenzamide390

1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine55 from Example 11a was reacted with benzoyl chloride (1.2 eq) followedby Suzuki coupling of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure K. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 59.5 mg of 390 after RP-HPLC,purification (72% yield). MS (Q1) 485.3 (M)+

Example 315N-((2-(1H-indazol-4-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-methylsulfonyl-methanamine391

1-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine56 from Example 11b was reacted with methanesulfonylchloride (1.2 eq)followed by Suzuki coupling of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure K. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 31.0 mg of 391 after RP-HPLCpurification (29% yield). MS (Q1) 473.2 (M)+

Example 316N-((2-(1H-indol-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-methylacetamide392

1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine55 from Example 11a was reacted with acetyl chloride (1.2 eq) followedby Suzuki coupling of indole-5-boronic acid as per General Procedure K.Complete reaction was confirmed by LCMS and the reaction wasconcentrated in vacuo to give 33.1 mg of 392 after RP-HPLC purification(44% yield). MS (Q1) 422.2 (M)+

Example 317N-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)phenyl)acetamide393

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 was reacted with3-acetamidophenylboronic acid via General Procedure C to give thecorresponding intermediate, after purification by flash chromatography,which was then reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A again to give, after purification by reverse HPLC,393. MS (Q1) 471 (M⁺)

Example 3182-(1H-indazol-4-yl)-6-(3-(methylsulfonyl)phenyl)-4-morpholinothieno[2,3-d]pyrimidine394

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 was reacted with3-methylsulfonylphenylboronic acid via General Procedure A to give thecorresponding intermediate, after purification by flash chromatography,which was then reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A again to give, after purification by reverse HPLC,394. MS (Q1) 507 (M⁺)

Example 3197-methyl-6-(3-(methylsulfonyl)phenyl)-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidine395

2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine fromExample 12 (0.3 g, 0.8 mmol), 3-(methylsulfonyl)phenylboronic acid (0.3g, 1.5 mmol), and bis(triphenylphosphine)palladium(II) dichloride (30mg, 40 μmol) in 1 M aqueous Na₂CO₃ (1.5 mL) and acetonitrile (1.5 mL)were heated to 100° C. in a sealed microwave reactor for 10 min. Uponcompletion,5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(0.4 g, 1.7 mmol), and bis(triphenylphosphine)palladium(II) dichloride(30 mg, 40 μmol) were added into the same pot. The reaction mixture washeated to 150° C. in a sealed microwave reactor for 20 min. The mixturewas extracted with EtOAc and CH₂Cl₂. The combined organics wereconcentrated to yield 395 after reverse phase HPLC purification (82 mg).MS (Q1) 506 (M)+

Example 3202-(1H-indazol-4-yl)-6-(4-methoxypyridin-3-yl)-4-morpholinothieno[2,3-d]pyrimidine396

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 was reacted with4-methoxypyridin-3-yl-3-boronic acid via General Procedure C to give thecorresponding intermediate, after purification by flash chromatography,which was then reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A again to give, after purification by reverse HPLC,396. MS (Q1) 445 (M⁺)

Example 3212-(1H-indazol-4-yl)-6-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine397

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 was reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via GeneralProcedure A to give the corresponding intermediate, after purificationby flash chromatography, which was then reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A again to give, after purification by reverse HPLC,397. MS (Q1) 453 (M⁺)

Example 3222-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylsulfonylpropan-2-amine398

To a solution of2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-amine (400mg, 1.3 mmol) in CH₂Cl₂ (20 mL) was added Et₃N (630 μL, 4.5 mmol) andmethanesulfonyl chloride (200 μL, 2.6 mmol). The resulting mixturestirred at room temperature overnight. The reaction was quenched by theaddition of saturated aqueous NaHCO₃. The organic layer was separatedand the aqueous layer was extracted with EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude material was purified by silica gel chromatography (0-100% EtOAcin hexane). A portion (0.1 mmol) of the resulting pure product wasutilized in a Suzuki coupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide398 after reverse phase HPLC purification (8 mg). MS (Q1) 473 (M)+

Example 323N-(2-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-yl)acetamide399

To a solution of2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-amine (400mg, 1.3 mmol) in CH₂Cl₂ (20 mL) was added Et₃N (630 μL, 4.5 mmol) andacetyl chloride (180 μL, 2.6 mmol). The resulting mixture stirred atroom temperature overnight. The reaction was quenched by the addition ofsaturated aqueous NaHCO₃. The organic layer was separated and theaqueous layer was extracted with EtOAc. The combined organic layers weredried over Na₂SO₄, filtered, and concentrated in vacuo. The crudematerial was purified by silica gel chromatography (0-100% EtOAc inhexane). A portion (0.2 mmol) of the resulting pure product was utilizedin a Suzuki coupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide399 after reverse phase HPLC purification (36 mg). MS (Q1) 437 (M)+

Example 3242-(1H-indazol-4-yl)-4-morpholino-6-(6-morpholinopyridin-3-yl)thieno[3,2-d]pyrimidine400

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 was reacted with4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholinevia General Procedure A to give the corresponding intermediate, afterpurification by flash chromatography, which was then reacted with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 viaGeneral Procedure A again to give, after purification by reverse HPLC,400. MS (Q1) 500 (M⁺)

Example 3252-(1H-indazol-4-yl)-6-(2-(4-N-methylsulfonylpiperazin-1-yl)propan-2-yl)-4-morpholinothieno[3,2-d]pyrimidine401

To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (6 gmg) in THF (300 mL) at −78° C. was added n-butyllithium (11.3 mL of a2.5 M solution in hexanes) and the reaction stirred at −78° C. for 1 h.Carbon dioxide gas was then bubbled slowly through the reaction mixturefor several minutes. The reaction mixture was warmed slowly to roomtemperature. THF was reduced in vacuo and the residue was dissolved insodium bicarbonate solution, washed with ethyl acetate, and the basicphase was then carefully acidified to pH 3, yielding a pale precipitatewhich was collected by filtration. Air drying yielded2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxylic acid (5.5g).

To a solution of2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxylic acid (2.0g) in DMF (50 mL) was added 1,1-carbonyldiimidazole (2.16 g). After 1hour, triethylamine (2.8 ml) and 1-methanesulfonyl-piperazinehydrochloride salt (2.7 g) were added. After stirring overnight, waterwas added and(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-(4-methanesulfonyl-piperazin-1-yl)-methanonewas collected as a white solid by filtration.

(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-(4-methanesulfonyl-piperazin-1-yl)-methanone(1.8 g) was dissolved in THF (40 mL) at −10° C. and zirconium chloride(4.7 g) was added. After stirring for one hour, methyl magnesium bromide(3M solution in ether, 8.1 mL) was added dropwise. After 24 hours, thereaction mixture was quenched with water, extracted with EtOAc, dried(MgSO₄) and the solvent was removed in vacuo. The residue was purifiedusing flash chromatography to yield2-chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-1-methyl-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine(100 mg).

2-Chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-1-methyl-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidinewas reacted with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in GeneralProcedure A. Purification by column chromatography yielded 401. (400 MHzCDCl3): 1.48 (6H, s, CH3), 2.66-2.68 (4H, m, CH2), 2.75 (3H, s, CH3),3.21 (4H, m, CH2), 3.86-3.88 (4H, m, CH2), 4.01-4.04 (4H, m, CH2), 7.29(1H, s, ar), 7.42-7.46 (1H, m, ar), 7.53 (1 h, d (J=8.33), ar), 8.21 (1h, d (J=7.09), ar), 8.95 (1H, s, ar), 10.04 (1H, b, NH). MH+=542.46

Example 3262-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carbonitrile402

A solution of 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19from Example 12 (0.2 g, 0.5 mmol) and CuCN (50 mg, 0.6 mmol) in pyridine(1 mL) was heated at 115° C. for 2 h then cooled to room temperature andstirred 18 h. The reaction was poured into 1 M HCl and ice and theaqueous layer was extracted with CH₂Cl₂. The product was purified bysilica gel chromatography (0-75% EtOAc in hexane) to provide2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbonitrile (35 mg).

2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbonitrile (35 mg) wasreacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole7 (6 mg) by Suzuki coupling according to the General Procedure A to give402. MS (Q1) 363 (M)+

Example 327N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-methoxy-N-methylacetamide403

1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine55 from Example 1a (0.22 g) was reacted with methoxyacetyl chloride (1.2eq) followed by Suzuki coupling of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure K. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 52.7 mg of 403 after RP-HPLCpurification (52% yield). MS (Q1) 453.2 (M)+

Example 328(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(4-(methylthio)phenyl)methanol404

To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (2.74g) in THF (40 mL) at −78° C. was added n-butyllithium (5.15 mL of a 2.5M solution in hexanes) and the reaction stirred at −78° C. for 1 h.4-Methylmercaptobenzaldehyde (1.43 mL) was then added and the reactionmixture was lowly warmed to room temperature. Water was added and theresulting precipitate was collected by filtration. Recyrstallisationfrom EtOAc/hexane yielded(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-(4-methylsulfanyl-phenyl)-methanol(2.53 g).

(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-(4-methylsulfanyl-phenyl)-methanolwas reacted with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in generalprocedure A. Purification by column chromatography yielded 404. (400MHz, CDCl3): 2.52 (3H, s, CH3), 2.60 (1H, m, CH), 3.91-3.93 (4H, m,CH2), 4.09-4.11 (4H, m, CH2), 6.15 (1H, b, OH), 7.30 (1H, m, ar), 7.33(1H, m, ar), 7.35 (1H, m, ar), 7.43 (1H, m, ar), 7.46 (1H, m, ar), 7.51(1H, m, ar), 7.59 (1H, m, ar), 8.38 (1H, d, ar), 9.02 (1H, s, ar), 10.10(1H, b, NH). (M+H)+ 490.27

Example 329(2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)-N-methylsulfonyl,N-methylmethanamine405

(2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)-n-methyl-N-(methylsulfonyl)methaneamine(56% yield; MS (Q1) 377 (M)+) prepared following General Procedure H,and 1H-pyrrolo[2,3-b]pyridine boronic pinacol ester were reactedfollowing General Procedure A to produce 405 in 3.6% yield MS (Q1) 459.1(M)+

Example 330N-((2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N-methylacetamide406

N-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)-N-methylacetamide(68% yield; MS (Q1) 341.1 (M)+) prepared following General Procedure H,and 1H-pyrrolo[2,3-b]pyridine boronic pinacol ester were reactedfollowing General Procedure A to produce 406 in 35.5% yield MS (Q1)384.5 (M)+

Example 331N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-hydroxy-N,2-dimethylpropanamide407

1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine55 from Example 11a (0.22 g) was reacted with 2-acetoxyisobutyrylchloride (1.2 eq) followed by suzuki coupling of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as pergeneral procedure K. The resulting compound was dissolved in 2 mL THFand 2 mL MeOH followed by the addition of 2 mL 1M liOH and the resultingsolution stirred for 2.5 hours. Complete reaction was confirmed by LCMSand the reaction was concentrated in vacuo to give 80.2 mg of 407 afterRP-HPLC purification (52% yield). MS (Q1) 467.2 (M)+

Example 332N-((2-(1H-indazol-4-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-methylacetamide408

1-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine56 from Example 11b was reacted with acetyl chloride (1.2 eq) followedby Suzuki coupling of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure K. Complete reaction was confirmed by LCMS and thereaction was concentrated in vacuo to give 101.9 mg of 408 after RP-HPLCpurification (40% yield). MS (Q1) 437.2 (M)+.

Example 333N-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-hydroxy-N-methylacetamide409

1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine55 from Example 11a (0.22 g) was reacted with acetoxyacetyl chloride(1.2 eq) followed by Suzuki coupling of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as perGeneral Procedure K. The resulting compound was dissolved in 2 mL THFand 2 mL MeOH followed by the addition of 2 mL 1M LiOH and the resultingsolution stirred for 2.5 hours. Complete reaction was confirmed by LCMSand the reaction was concentrated in vacuo to give 31.1 mg of 409 afterRP-HPLC purification (24% yield). MS (Q1) 439.2 (M)+.

Example 334N-(2-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-yl)nicotinamide410

To a solution of2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-amine (150mg, 0.5 mmol) in CH₂Cl₂ (10 mL) was added Et₃N (450 μL, 3.2 mmol) andnicotinoyl chloride hydrochloric acid (160 mg, 0.9 mmol). The resultingmixture stirred at room temperature overnight. The reaction was quenchedby the addition of saturated aqueous NaHCO₃. The organic layer wasseparated and the aqueous layer was extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated invacuo. A portion (0.2 mmol) of the resulting crude product was utilizedin a Suzuki coupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 to provide410 after reverse phase HPLC purification (22 mg). MS (Q1) 500 (M)+

Example 335N-(2-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-yl)-3-methoxybenzamide411

To a solution of2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-amine (150mg, 0.5 mmol) in CH₂Cl₂ (10 mL) was added Et₃N (230 μL, 1.6 mmol) andm-anisoyl chloride (160 mg, 0.9 mmol). The resulting mixture stirred atroom temperature overnight. The reaction was quenched by the addition ofsaturated aqueous NaHCO₃. The organic layer was separated and theaqueous layer was extracted with EtOAc. The combined organic layers weredried over Na₂SO₄, filtered, and concentrated in vacuo. A portion (0.2mmol) of the resulting crude product was utilized in a Suzuki couplingusing General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide411 after reverse phase HPLC purification (13 mg). MS (Q1) 529 (M)+

Example 336N-(2-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-yl)-4-methoxybenzamide412

To a solution of2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-amine (150mg, 0.5 mmol) in CH₂Cl₂ (10 mL) was added Et₃N (230 μL, 1.6 mmol) andthe HCl salt of p-anisoyl chloride (160 mg, 0.9 mmol). The resultingmixture stirred at room temperature overnight. The reaction was quenchedby the addition of saturated aqueous NaHCO₃. The organic layer wasseparated and the aqueous layer was extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated invacuo. A portion (0.2 mmol) of the resulting crude material was utilizedin a Suzuki coupling using General Procedure A with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide412 after reverse phase HPLC purification (30 mg). MS (Q1) 529 (M)+

Example 337(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(4-(methylsulfonyl)phenyl)methanol413

To(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-(4-methylsulfanyl-phenyl)-methanol(712 mg) in DCM (50 mL) was added meta-chloroperbenzoic acid (820 mg) at0° C. After 4 hours, the reaction mixture was quenched with sodiumthiosulphate solution, extracted with DCM, dried (MgSO₄) and the solventremoved in vacuo. The residue was purified using flash chromatography toyield(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-(4-methanesulfonyl-phenyl)-methanol.

(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-(4-methanesulfonyl-phenyl)-methanolwas reacted with4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in GeneralProcedure A. Purification by column chromatography yielded 413. (400MHz, CDCl3): 3.00 (3H, s, CH3), 3.82-3.84 (4H, m, CH2), 3.99-4.01 (4H,m, CH2), 6.21 (1H, b, NH), 7.29 (1H, d (J=0.80), ar), 7.43 (1H, t(J=7.80), ar), 7.53 (1H, d (J=8.30), ar), 7.66 (2H, d (J=8.26), ar),7.91 (2H, d (J=8.46), ar), 8.18 (1H, d (J=6.56), ar), 8.91 (1H, s, ar).(M+H)+ 522.21

Example 3382-(2-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)propan-2-ol414

2-(2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)propan-2-ol (100 mg)was reacted with 161 mg of3-((2-(trimethylsilyl)ethoxy)methyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine54 via Example 6b and General Procedure A. Crude2-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)propan-2-olwas then refluxed overnight with 2 equivalents oftetrabutylammoniumfluoride in THF to remove the SEM protecting group.The crude material was then extracted with water and ethyl acetate. Theorganic layer was concentrated to dryness and then purified via reversephase HPLC to give 5.1 mg of 414. MS (Q1) 411.2 (M)+

Example 339(S)-1-(3-(7-methyl-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6-yl)phenylsulfonyl)propan-2-ol415

(S)-1-(3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylsulfonyl)propan-2-ol(10 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 38 mg of 415. MS (Q1) 550.0 (M)⁺

Example 3407-methyl-6-(3-(N-morpholino)sulfonyl)phenyl)-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidine416

2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine (70 mg) wascoupled to N-morpholinyl-3-boronobenzene sulfonamide, and then reactedwith 7-azaindole-5-boronic acid pinacol ester via General Procedure F.The product was purified by reverse phase HPLC to yield 39 mg of 416. MS(Q1) 577.0 (M)⁺

Example 341N-methyl,N-methylsulfonyl(4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[2,3-d]pyrimidin-6-yl)methanamine417

(2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl-n-methyl-N-(methylsulfonyl)methaneamineand 1H-pyrrolo[2,3-b]pyridin-5-yl-5-boronic acid were reacted followingGeneral Procedure A to produce 417 in 6.0% yield MS (Q1) 459.2 (M)+

Example 342 6-(3-(methylsulfonyl)phenyl)-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidine 418

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 from Example 12(0.2 g, 0.6 mmol), 3-(methylsulfonyl)phenylboronic acid (120 mg, 0.6mmol), and bis(triphenylphosphine)palladium(II) dichloride (20 mg, 30μmol) in 1M aqueous Na₂CO₃ (1 mL) and acetonitrile (1 mL) were heated to100° C. in a sealed microwave reactor for 10 min. Upon completion,5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(210 mg, 0.87 mmol) and bis(triphenylphosphine)palladium(II) dichloride(20 mg, 30 μmol) were added and the mixture was heated to 150° C. in asealed microwave reactor for 20 min. The mixture was extracted withEtOAc and CH₂Cl₂. The combined organics were concentrated to yield 418after reverse phase HPLC purification (40 mg). MS (Q1) 492 (M)+

Example 3434-morpholino-6-phenyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidine419

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 from Example 12(0.2 g, 0.6 mmol), phenylboronic acid (70 mg, 0.6 mmol), andbis(triphenylphosphine)palladium(II) dichloride (20 mg, 30 μmol) in 1 Maqueous Na₂CO₃ (1 mL) and acetonitrile (1 mL) were heated to 100° C. ina sealed microwave reactor for 10 min. Upon completion,5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(210 mg, 0.87 mmol) and bis(triphenylphosphine)palladium(II) dichloride(20 mg, 30 μmol) were added and the mixture was heated to 150° C. in asealed microwave reactor for 20 min. The mixture was extracted withEtOAc and CH₂Cl₂. The combined organics were concentrated to yield 419after reverse phase HPLC purification (45 mg). MS (Q1) 414 (M)+

Example 3447-methyl-4-morpholino-6-phenyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidine420

2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine fromExample 12 (0.2 g, 0.5 mmol), phenylboronic acid (60 mg, 0.5 mmol), andbis(triphenylphosphine)palladium(II) dichloride (18 mg, 25 μmol) in 1 Maqueous Na₂CO₃ (1 mL) and acetonitrile (1 mL) were heated to 100° C. ina sealed microwave reactor for 10 min. Upon completion,5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(180 mg 0.75 mmol) and bis(triphenylphosphine)palladium(II) dichloride(13 mg, 20 μmol) were added and the mixture was heated to 150° C. in asealed microwave reactor for 20 min. The mixture was extracted withEtOAc and CH₂Cl₂. The combined organics were concentrated to yield 420after reverse phase HPLC purification (57 mg). MS (Q1) 428 (M)+

Example 345(2S)-2-hydroxy-N-((3-(7-methyl-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6-yl)phenyl)methyl)propanamide421

Crude(2S)-N-(3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)methyl-2-hydroxypropanamide(65 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 48.4 mg of 421. MS (Q1) 529.2 (M)⁺

Example 3462-(4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6-yl)propan-2-ol422

To 209 mg of 12 in 2 mL 1M KOAc and 2 mL acetonitrile, was added 195.2mg (1.2 eq) of 7-azaindole-5-boronic acid pinacol ester and 77.4 mg (0.1eq) of Pd(PPh₃)₄ as per General Procedure A to give 99.2 mg of 422 afterRP-HPLC purification (75% yield). MS (Q1) 396.2 (M)+

Example 3477-methyl-6-(3-(2-hydroxyethylaminosulfonyl)phenyl)-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidine423

2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine (50 mg) wascoupled to N-(2-hydroxyethyl)-3-boronobenzene sulfonamide, and thenreacted with 7-azaindole-5-boronic acid pinacol ester via GeneralProcedure F. The product was purified by reverse phase HPLC to yield17.7 mg of 423. MS (Q1) 551.1 (M)⁺

Example 348N-methylsulfonyl(3-(7-methyl-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6-yl)phenyl)methanamine424

2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine (50 mg) wascoupled to 3-methanesulphonylamino methyl benzeneboronic acid, and thenreacted with 7-azaindole-5-boronic acid pinacol ester via GeneralProcedure F. The product was purified by reverse phase HPLC to yield34.5 mg of 424. MS (Q1) 535.2 (M)⁺

Example 349(4-hydroxypiperidin-1-yl)(3-(7-methyl-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6-yl)phenyl)methanone425

3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoicacid (60 mg) was reacted with 4-hydroxypiperidine via General ProcedureB to yield3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-hydroxypiperidin-1-yl)methanone.Crude3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-hydroxypiperidin-1-yl)methanone(72 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 29.5 mg of 425. MS (Q1) 555.2 (M)+

Example 350N-(2-hydroxyethyl)-3-(7-methyl-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6-yl)benzamide426

3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoicacid (60 mg) was reacted with ethanolamine via General Procedure B toyield3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-hydroxyethyl)benzamide.Crude3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-hydroxyethyl)benzamide(74 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 2.6 mg of 426. MS (Q1) 515.2 (M)⁺

Example 351(3-(7-methyl-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone427

3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoicacid (60 mg) was reacted with 1-methylpiperizine via General Procedure Bto yield3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-methylpiperazin-1-yl)methanone.Crude3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-methylpiperazin-1-yl)methanone(67 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester viaGeneral Procedure A. The product was purified by reverse phase HPLC toyield 19.8 mg of 427. MS (Q1) 554.0 (M)⁺

Example 3524-morpholino-6-(6-morpholinopyridin-3-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidine428

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 was reacted with4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholinevia General Procedure A to give the corresponding intermediate, afterpurification by flash chromatography, which was then reacted with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridinevia General Procedure A again to give, after purification by reverseHPLC, 22 mg of 428. MS (Q1) 500 (M⁺)

Example 3534-(4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6-yl)thiazol-2-amine429

To a solution of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4, Example2) (1.0 eq) dissolved in THF (0.1M) at −78° C. was added a solution ofn-butyllithium (1.3 eq, 1.6M in hexanes) following General Procedure D.The reaction mixture was stirred at −40° C. for 30 minutes.N,N-dimethylacetamide (4.0 eq) was added and reaction mixture wasallowed to slowly warm up to 0° C. and stirred for 2 hours. Reactionmixture was poured in a cold solution of 0.25M HCl, and extracted withdichloromethane. The combined organic layers were dried (Na₂SO₄) andconcentrated. The crude reaction mixture was purified by flashchromatography to yield1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanone.

To a solution of1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanone (1.0 eq)dissolved in a mixture of CHCl₃, 33% wt HBr and acetic acid (1:1:1) at−0° C. was added a solution of Br₂ in CHCl₃ (1.05 eq). Reaction mixturewas stirred at −0° C. until completed, then extracted in dichloromethanewith saturated bicarbonate solution one time. The organic layer isdried, filtered and concentrated to yield the crude intermediate. Thisintermediate is purified by flash chromatography to yield2-bromo-1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanone.

To a solution of2-bromo-1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanone(1.0 eq) dissolved in EtOH was added thiourea. Reaction mixture washeated at 70° C. until completed, then extracted in dichloromethane withsaturated bicarbonate solution one time. The organic layer is dried,filtered and concentrated to yield the crude intermediate. Thisintermediate is purified by flash chromatography to yield4-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)thiazol-2-amine. MS(Q1) 413 (M⁺)

4-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)thiazol-2-amine wasreacted with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridinevia General Procedure B to give, after purification by reverse HPLC, 41mg of 429. MS (Q1) 436 (M⁺)

Example 3546-(7-methyl-6-(3-(methylsulfonyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-3H-imidazo[4,5-b]pyridine430

To 215 mg of4-(2-chloro-7-methyl-6-(3-(methylsulfonyl)phenyl)thieno[3,2-d]pyrimidin-4-yl)morpholinein 5 mL DMF in a microwave vial was added 0.41 g (1.5 eq) of 50 and 36mg (0.1 eq) of Pd(PPh₃)₂Cl₂ and the vial placed in a Biotage microwavereactor for 30 minutes at 150° C. Complete reaction was confirmed byLCMS. The reaction mixture was diluted with EtOAc, partitioned with 1 MHCl, and the EtOAc layer dried over MgSO₄ and concentrated in vacuo. Thecrude solid was purified by flash chromatography (EtOAc/Hexanes) to give0.22 g (69% yield) of protected product which was dissolved in 20 mL THFand 0.55 g TBAF (6.0 eq) and heated to 80° C. for 72 hours to remove theprotecting group. Complete deprotection was confirmed by LCMS and thereaction mixture was diluted with water, extracted with EtOAc, andconcentrated in vacuo to give 38.5 mg (22% yield) of 430 after RP-HPLCpurification. MS (Q1) 507.1 (M)+

Example 3552-(2-(1H-imidazo[4,5-b]pyridin-6-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol431

To 100 mg of 12 in 5 mL DMF in a microwave vial was added 0.26 g (1.5eq) of 50 and 22 mg (0.1 eq) of Pd(PPh₃)₂Cl₂ and the vial placed in abiotage microwave reactor for 20 minutes at 150° C. Reaction was notcomplete and 0.1 eq more Pd(PPh₃)₂Cl₂ was added and the mixture and itwas placed on the microwave again for 30 minutes at 150° C. Completereaction was confirmed by LCMS. The reaction mixture was diluted withwater and brine and the product extracted out with EtOAc andconcentrated in vacuo. The crude solid was purified by RP-HPLC to give431. MS (Q1) 397.2 (M)+

Example 3562-methyl-6-(7-methyl-6-(3-(methylsulfonyl)phenyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-3H-imidazo[4,5-b]pyridine432

To 120 mg of4-(2-chloro-7-methyl-6-(3-(methylsulfonyl)phenyl)thieno[3,2-d]pyrimidin-4-yl)morpholinoin 2 mL 1M KOAc and 2 mL acetonitrile was added 0.16 g (1.5 eq) of 54and 32 mg (0.1 eq) of Pd(PPh₃)₄ as per General Procedure A to give 180mg (99% yield) of the of the protected product after flashchromatography (EtOAc/Hexanes). MS (Q1) 652 (M)+. This compound wasdissolved in 10 mL THF and 0.45 g TBAF (6.0 eq) was added and thereaction heated to 90° C. overnight to remove the SEM protecting group.Complete deprotection was confirmed by LCMS and the reaction mixture wasdiluted with water, extracted with EtOAc, dried over MgSO₄ andconcentrated in vacuo to give 44.8 mg of 432 after RP-HPLC purification(46% yield). MS (Q1) 521 (M)+

Example 3572-(2-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol433

To 236 mg of compound 12 in 2 mL 1M KOAc and 2 mL acetonitrile was added0.44 g (1.5 eq) of 54 and 87 mg (0.1 eq) of Pd(PPh₃)₄ as per GeneralProcedure A to give 330 mg of the SEM adduct after RP-HPLC purification(81% yield). MS (Q1) 396.2 (M)+. This compound was dissolved in 10 mLTHF and 0.96 g TBAF was added and the reaction heated to 90° C.overnight to remove the SEM protecting group. Complete deprotection wasconfirmed by LCMS and the reaction mixture was diluted with water,extracted with EtOAc and a small amount of MeOH, washed with brine andconcentrated in vacuo to give 113.8 mg of 433 after RP-HPLC purification(46% yield). MS (Q1) 411.2 (M)+

Example 3585-(7-methyl-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6-yl)-N-(2-morpholinoethyl)pyridin-2-amine434

2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine (1 eq),2-fluoro-5-pyridineboronic acid (1.1 eq) andbis(triphenylphosphine)palladium(II) dichloride (0.1 eq) in 1M Na₂CO₃aqueous solution (3 eq) and an equal volume of acetonitrile was heatedto 100° C. in a sealed microwave reactor for 30 min. Reaction mixturewas concentrated, then crude product was purified by flashchromatography to give4-(2-chloro-6-(6-fluoropyridin-3-yl)-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholine.MS (Q1) 365 (M⁺)

4-(2-chloro-6-(6-fluoropyridin-3-yl)-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholinewas reacted with 2-morpholinoethylamino via General Procedure L to give,after purification by flash chromatography, the correspondingintermediate, which was then reacted with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridinevia General Procedure A to give, after purification by reverse HPLC, 40mg of 434. MS (Q1) 557 (M⁺)

Example 3593-(5-(7-methyl-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6-yl)pyridin-2-ylamino)propane-1,2-diol435

4-(2-chloro-6-(6-fluoropyridin-3-yl)-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholinewas reacted with 3-amino-1,2-propanediol via General Procedure L togive, after purification by flash chromatography, the correspondingintermediate, which was then reacted with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridinevia General Procedure A to give, after purification by reverse HPLC, 50mg of 435. MS (Q1) 518 (M⁺)

Example 3602-(2-(5-(7-methyl-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6-yl)pyridin-2-ylamino)ethoxy)ethanol436

4-(2-chloro-6-(6-fluoropyridin-3-yl)-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholinewas reacted with 2-(2-aminoethoxy)ethanol via General Procedure L togive, after purification by flash chromatography, the correspondingintermediate, which was then reacted with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridinevia General Procedure A to give, after purification by reverse HPLC, 52mg of 436. MS (Q1) 532 (M⁺)

Example 361N-methyl(4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)thieno[3,2-d]pyrimidin-6-yl)methanamine437

(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamineand5-(4,4,5,5-tetramethyl-[1.3.2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridinewere reacted according to the General Procedure A to give 437. NMR(DMSO, 400 MHz), 2.35 (3H, s), 3.78-3.82 (4H, m), 3.99-4.06 (6H, m),6.54 (1H, s) 7.36 (1H, s), 7.48-7.51 (1H, m), 8.97 (1H, s), 9.28 (1H,s). MS: (ESI+): MH+=381

Example 3621-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyrrolidin-2-one438

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine (150 mg), 90 μL of2-pyrrolidinone, potassium phosphate tribasic (250 mg), copper iodide (7mg), 4 μL of N,N-dimethylethylenediamine in 2 mL of 1,4-dioxane washeated to 100° C. for 16 h. The reaction mixture was evaporated and theresidue was diluted with ethyl acetate (60 mL), washed with brine (30mL), dried over MgSO₄, filtered and evaporated. The crude product waspurified on reverse phase HPLC to give 53 mg of1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyrrolidin-2-one.

1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyrrolidin-2-one (35mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole viaProcedure A. The product was purified by reverse phase HPLC to yield19.5 mg of 438. MS (Q1) 421 (M)⁺

Example 3633-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)oxazolidin-2-one439

N-Butyllithium (9.4 mL, 22.48 mmol, 2.5 M in hexane solution) was addedto a mixture of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine (3.0 g,11.74 mmol) in 60 mL of THF at −78° C. The reaction mixture was allowedto warm to −40° C. and stirred for 30 min. A solution of iodine (6.0 g,23.48 mmol) in 10 mL of THF was added dropwise. After the addition wascompleted. The reaction mixture was brought to room temperature andstirred for 2 h. The mixture was quenched by diluting withdichloromethane (300 mL) and extracting with H₂O (2×100 mL). The organiclayer was washed with Na₂S₂O₃ (2×100 mL), H₂O (2×100 mL), dried overMgSO₄, filtered and evaporated to afford2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine (3.4 g, 75%).

2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine (150 mg),2-oxazolidinone (103 mg), potassium phosphate tribasic (250 mg), copperiodide (7 mg), 4 μL of N,N-dimethylethylenediamine in 2 mL of1,4-dioxane was heated to 100° C. for 15 hr. The reaction mixture wasevaporated and the residue was diluted with ethyl acetate (50 mL),washed with brine (30 mL), dried over MgSO₄, filtered and evaporated.The crude product was purified on reverse phase HPLC to give 46 mg of3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl) oxazolidin-2-one.

3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)oxazolidin-2-one (46mg) was coupled to4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole viaProcedure A. The product was purified by reverse phase HPLC to yield 8.6mg of 439. MS (Q1) 423 (M)⁺

Example 364 p110α (Alpha) PI3K Binding Assay

Binding Assays: Initial polarization experiments were performed on anAnalyst HT 96-384 (Molecular Devices Corp, Sunnyvale, Calif.). Samplesfor fluorescence polarization affinity measurements were prepared byaddition of 1:3 serial dilutions of p110alpha PI3K (Upstate CellSignaling Solutions, Charlottesville, Va.) starting at a finalconcentration of 20 ug/mL in polarization buffer (10 mM Tris pH 7.5, 50mM NaCl, 4 mM MgCl₂, 0.05% Chaps, and 1 mM DTT) to 10 mM PIP₂(Echelon-Inc., Salt Lake City, Utah) final concentration. After anincubation time of 30 minutes at room temperature, the reactions werestopped by the addition of GRP-1 and PIP3-TAMRA probe (Echelon-Inc.,Salt Lake City, Utah) 100 nM and 5 nM final concentrations respectively.Read with standard cut-off filters for the rhodamine fluorophore(λex=530 nm; λem=590 nm) in 384-well black low volume Proxiplates(PerkinElmer, Wellesley, Mass.) Fluorescence polarization values wereplotted as a function of the protein concentration, and the EC₅₀ valueswere obtained by fitting the data to a 4-parameter equation usingKaleidaGraph software (Synergy software, Reading, Pa.). This experimentalso establishes the appropriate protein concentration to use insubsequent competition experiments with inhibitors.

Inhibitor IC₅₀ values were determined by addition of the 0.04 mg/mL p110alpha PI3K (final concentration) combined with PIP₂ (10 mM finalconcentration) to wells containing 1:3 serial dilutions of theantagonists in a final concentration of 25 mM ATP (Cell SignalingTechnology, Inc., Danvers, Mass.) in the polarization buffer. After anincubation time of 30 minutes at room temperature, the reactions werestopped by the addition of GRP-1 and PIP3-TAMRA probe (Echelon-Inc.,Salt Lake City, Utah) 100 nM and 5 nM final concentrations respectively.Read with standard cut-off filters for the rhodamine fluorophore(λex=530 nm; λem=590 nm) in 384-well black low volume proxi plates(PerkinElmer, Wellesley, Mass.) Fluorescence polarization values wereplotted as a function of the antagonist concentration, and the IC₅₀values were obtained by fitting the data to a 4-parameter equation inAssay Explorer software (MDL, San Ramon, Calif.).

Alternatively, inhibition of PI3K was determined in a radiometric assayusing purified, recombinant enzyme and ATP at a concentration of 1 uM.The compound was serially diluted in 100% DMSO. The kinase reaction wasincubated for 1 h at room temperature, and the reaction was terminatedby the addition of PBS. IC₅₀ values were subsequently determined usingsigmoidal dose-response curve fit (variable slope).

Example 365 p110 Isoform Selectivity Scintillation Proximity BindingAssay

The ability of Formula Ia and Ib compounds from Tables 1a and 1b toinhibit the lipid kinase activity of purified preparations of human PI3Kisoforms alpha, beta, delta, and gamma was determined by a radiometricscintillation proximity assay (SPA, GE Healthcare, AmershamBiosciences). Concentration dependent inhibition at 50% (IC₅₀ μMol) wasdetermined for all four isoforms (alpha) and fold potency over beta,delta, and gamma relative to alpha was calculated for a selection ofcompounds in Table 2. Each compound has a p110 alpha IC₅₀<1 μMol.

TABLE 2 alpha/ alpha/ alpha/ compound beta delta gamma 101 >10 <10 >10133 <10 <10 >10 137 >10 <10 <10 170 <10 <10 <10 202 <10 <10 >10 203 <10<10 >10 205 <10 <10 >10 208 >10 <10 >10 218 >10 <10 >10 226 <10 <10 >10233 >10 <10 <10 235 >10 <10 >10 237 >10 <10 >10 238 >10 <10 >10 257 <10<10 >10 263 <10 <10 >10 265 >10 <10 >10 304 10 <10 >10 305 <10 <10 >10312 <10 <10 >10 321 >10 <10 >10 324 >10 <10 >10 334 >10 <10 >10 336 >10<10 >10 338 >10 <10 >10 353 <10 <10 >10 360 >10 >10 >10 368 <10 <10 >10388 >10 <10 >10 390 <10 <10 <10 395 >10 >10 >10 417 >10 >10 >10 418 >1010 >10 422 >10 <10 >10 428 >10 >10 >10 429 >10 >10 >10

Example 366 In vitro Cell Proliferation Assay

Efficacy of Formula Ia and Ib compounds were measured by a cellproliferation assay employing the following protocol (Promega Corp.Technical Bulletin TB288; Mendoza et al (2002) Cancer Res.62:5485-5488):

-   1. An aliquot of 100 μl of cell culture containing about 10⁴ cells    (PC3, Detroit562, or MDAMB361.1) in medium was deposited in each    well of a 384-well, opaque-walled plate.-   2. Control wells were prepared containing medium and without cells.-   3. The compound was added to the experimental wells and incubated    for 3-5 days.-   4. The plates were equilibrated to room temperature for    approximately 30 minutes.-   5. A volume of CellTiter-Glo Reagent equal to the volume of cell    culture medium present in each well was added.-   6. The contents were mixed for 2 minutes on an orbital shaker to    induce cell lysis.-   7. The plate was incubated at room temperature for 10 minutes to    stabilize the luminescence signal.-   8. Luminescence was recorded and reported in graphs as RLU=relative    luminescence units.

Alternatively, cells were seeded at optimal density in a 96 well plateand incubated for 4 days in the presence of test compound. Alamar Blue™was subsequently added to the assay medium, and cells were incubated for6 h before reading at 544 nm excitation, 590 nm emission. EC₅₀ valueswere calculated using a sigmoidal dose response curve fit.

Example 367 Caco-2 Permeability

Caco-2 cells were seeded onto Millipore Multiscreen plates at 1×10⁵cells/cm², and were cultured for 20 days. Assessment of compoundpermeability was subsequently conducted. The compounds were applied tothe apical surface (A) of cell monolayers and compound permeation intothe basolateral (B) compartment was measured. This was performed in thereverse direction (B−A) to investigate active transport. A permeabilitycoefficient value, P_(app), for each compound, a measure of the rate ofpermeation of the compound across the membrane, was calculated.Compounds were grouped into low (P_(app)</=1.0×10⁶ cm/s) or high(P_(app)>/=1.0×10⁶ cm/s) absorption potential based on comparison withcontrol compounds with established human absorption.

For assessment of a compound's ability to undergo active efflux, theratio of basolateral (B) to apical (A) transport compared with A to Bwas determined. Values of B−A/A−B>/=1.0 indicated the occurrence ofactive cellular efflux. The had P_(app) values>/=1.0×10⁶ cm/s.

Example 368 Hepatocyte Clearance

Suspensions of cryopreserved human hepatocytes were used. Incubationswere performed at compound concentration of 1 mM or 3 μM at a celldensity of 0.5×10⁶ viable cells/mL. The final DMSO concentration in theincubation was 0.25%. Control incubations were also performed in theabsence of cells to reveal any non-enzymatic degradation. Duplicatesamples (50 μL) were removed from the incubation mixture at 0, 5, 10,20, 40 and 60 minutes (control sample at 60 minutes only) and added tomethanol-containing internal standard (100 μL)—to terminate thereaction. Tolbutamide, 7-hydroxycoumarin, and testosterone were used ascontrol compounds. Samples were centrifuged and the supernatants at eachtime point pooled for analysis by LC-MSMS. From a plot of ln peak arearatio (parent compound peak area/internal standard peak area) againsttime, intrinsic clearance (CL_(int)) was calculated as follows: CL_(int)(μl/min/million cells)=V×k, where k is the elimination rate constant,obtained from the gradient of ln concentration plotted against time; Vis a volume term derived from the incubation volume and is expressed asuL 10⁶ cells⁻¹.

Compounds from Tables 1a and 1b were characterized on the basis of low(CL</=4.6 μL/min/10⁶ cells), medium (CL>/=4.6; </=25.2 μl/min/10⁶ cells)and high (>/=25.2 μl/min/10⁶ cells) hepatocyte clearance.

Example 369 Cytochrome P450 Inhibition

Certain compound of the invention was screened against five CYP450targets (1A2, 2C9, 2C19, 2D6, 3A4) at 10 concentrations in duplicate,with a top concentration of 100 uM being used. Standard inhibitors(furafylline, sulfaphenazole, tranylcypromine, quinidine, ketoconazole)were used as controls. Plates were read using a BMG LabTechnologiesPolarStar in fluorescence mode.

Example 370 Cytochrome P450 Induction

Freshly isolated human hepatocytes from a single donor were cultured for48 h prior to addition of test compound at three concentrations and wereincubated for 72 h. Probe substrates for CYP3A4 and CYP1A2 were addedfor 30 minutes and 1 h before the end of the incubation. At 72 h, cellsand media were removed and the extent of metabolism of each probesubstrate quantified by LC-MS/MS. The experiment was controlled by usinginducers of the individual P450s incubated at one concentration intriplicate to determine the extent of induction of cytochrome P450enzymes.

Example 371 Plasma Protein Binding

Solutions of test compound (5 um, 0.5% final DMSO concentration) wereprepared in buffer and 10% plasma (v/v in buffer). A 96 well HT dialysisplate was assembled so that each well was divided in two by asemi-permeable cellulose membrane. The buffer solution was added to oneside of the membrane and the plasma solution to the other side;incubations were then conducted at 37° C. over 2 h in triplicate. Thecells were subsequently emptied, and the solutions for each batch ofcompounds were combined into two groups (plasma-free andplasma-containing) then analysed by LC-MSMS using two sets ofcalibration standards for plasma-free (6 points) and plasma-containingsolutions (7 points). The fraction unbound value for the compounds ofTables 1a and 1b was calculated as: highly protein bound compounds(>/=90% bound) had an Fu</=0.1.

Example 372 HERG Channel Blockage

The compounds of Tables 1a and 1b were evaluated for modulation ofrubidium efflux from HEK-294 cells stably expressing HERG potassiumchannels using established flux methodology. Cells were prepared inmedium containing RbCl and were plated into 96-well plates and grownovernight to form monolayers. The efflux experiment was initiated byaspirating the media and washing each well with 3×100 μL ofpre-incubation buffer (containing low [K⁺]) at room temperature.Following the final aspiration, 50 μL of working stock (2×) compound wasadded to each well and incubated at room temperature for 10 minutes. 50μL of stimulation buffer (containing high [K⁺]) was then added to eachwell giving the final test compound concentrations. Cell plates werethen incubated at room temperature for a further 10 minutes. 80 μL ofsupernatant from each well was then transferred to equivalent wells of a96-well plate and analysed via atomic emission spectroscopy. Thecompound was screened as 10pt duplicate IC₅₀ curves, n=2, from a topconcentration of 100 μM.

The foregoing description is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will be readily apparent to those skilled in the art, it is notdesired to limit the invention to the exact construction and processshown as described above. Accordingly, all suitable modifications andequivalents may be considered to fall within the scope of the inventionas defined by the claims that follow.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

1. A compound selected from Formula Ia and Formula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is H; R² is selectedfrom H, F, Cl, Br, I, CN, CF₃, —NO₂, —C(═Y)R¹⁰, —C(═Y)OR¹⁰,—C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, —OC(═Y)R¹⁰, —OC(═Y)NR¹⁰R¹¹,—OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹), SR¹⁰, —S(O)R¹⁰,—S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰), —SC(═Y)R¹⁰,—SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, and C₁-C₂₀heteroaryl; R³ is fused bicyclic C₄-C₂₀ heterocyclyl or fused bicyclicC₁-C₂₀ heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl,C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ together with thenitrogen to which they are attached optionally form a saturated,partially unsaturated or fully unsaturated C₃-C₂₀ heterocyclic ringoptionally containing one or more additional ring atoms selected from N,O or S, wherein said heterocyclic ring is optionally substituted withone or more groups independently selected from oxo, (CH₂)_(m)OR¹⁰,NR¹⁰R¹¹, CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰, NR¹²C(═Y)R¹¹,NR¹²S(O)₂R¹¹, C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl and C₁-C₂₀heteroaryl; R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂ alkyl,or —(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms to which theyare attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR⁴R⁵)_(t)—NR¹⁰R¹¹; Y isO, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6; n is 1, 2, 3, 4, 5 or 6; andt is 2, 3, 4, 5 or
 6. 2. A compound selected from Formula Ia and FormulaIb:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is—(CR¹⁴R¹⁵)^(n)NR¹²S(O)₂R¹⁰ where n is 1 or 2; R¹², R¹⁴, and R¹⁵ areindependently selected from H and C₁-C₁₂ alkyl; and R¹⁰ is C₁-C₁₂ alkylor C₆-C₂₀ aryl; R² is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂,—C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —CR¹⁴R¹⁵)_(n)OR¹⁰, —(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰,—NR¹²C(═Y)OR¹⁰, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰, —OC(═Y)R¹⁰,—OC(═Y)OR¹⁰, —OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹),—OP(OR¹⁰)(OR¹¹), SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰),—S(O)₂(OR¹⁰), —SC(═Y)R¹⁰, SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl,C₂-C₈ alkenyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl; R³ is fused bicyclic C₄-C₂₀ heterocyclyl or fusedbicyclic C₁-C₂₀ heteroaryl; R₁₀, R¹¹ and R¹² are independently H, C₁-C₁₂alkyl, C₂-C₈ alkenyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ together with the nitrogen towhich they are attached optionally form a saturated, partiallyunsaturated or fully unsaturated C₃-C₂₀ heterocyclic ring optionallycontaining one or more additional ring atoms selected from N, O or S,wherein said heterocyclic ring is optionally substituted with one ormore groups independently selected from oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹,CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰, NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹,C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl and C₁-C₂₀ heteroaryl; R¹⁴and R¹⁵ are independently selected from H, C₁-C₁₂ alkyl, or—(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms to which theyare attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰,═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰, —OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰),—OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹), SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)(OR¹⁰), —SC(═Y)R¹⁰, —SC(═Y)OR¹⁰,—SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substituted alkyl, C₂-C₈ optionallysubstituted alkenyl, C₂,-C₈ optionally substituted alkynyl, C₃-C₁₂optionally substituted carbocyclyl, C₂-C₂₀ optionally substitutedheterocyclyl, C₆-C₂₀ optionally substituted aryl, C₁-C₂₀ optionallysubstituted heteroaryl, —(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and(CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Y is O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6; nis 1, 2, 3, 4, 5 or 6; and t is 2, 3, 4, 5 or
 6. 3. A compound selectedfrom Formula Ia and Formula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is —(CR¹⁴R¹⁵)_(n)OR¹⁰where n is 1 or 2, and R¹⁰, R¹⁴, and R¹⁵ are independently selected fromH and C₁-C₁₂ alkyl; R² is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂,—C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹,—NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰,—OC(═Y)R¹⁰, —OC(═Y)OR¹⁰, —OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰),—OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹), SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰), —SC(═Y)R¹⁰, —SC(═Y)OR¹⁰,—SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, and C₁-C₂₀ heteroaryl; R³is fused bicyclic C₄-C₂₀ heterocyclyl or fused bicyclic C₁-C₂₀heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ together with the nitrogen towhich they are attached optionally form a saturated, partiallyunsaturated or fully unsaturated C₃-C₂₀ heterocyclic ring optionallycontaining one or more additional ring atoms selected from N, O or S,wherein said heterocyclic ring is optionally substituted with one ormore groups independently selected from oxo, (C₂)_(m)OR¹⁰, NR¹⁰R¹¹, CF₃,F, Cl, Br, I, SO₂R¹⁰, C(═Y)R¹⁰, NR¹²C(═Y)R¹¹, NR¹²S(O)_(2R)R¹¹,C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl and C₁-C₂₀ heteroaryl; R¹⁴and R¹⁵ are independently selected from H, C₁-C₁₂ alkyl, or—(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms to which theyare attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR₁₀R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl, _(—(CR) ¹⁴ _(R)¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)_(t)NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and(CR¹⁴R¹⁵)_(t)NR¹⁰R¹¹; Y is O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6; nis 1, 2, 3, 4, 5 or 6; and t is 2, 3, 4, 5 or
 6. 4. A compound selectedfrom Formula Ia and Formula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is—(CR¹⁴R¹⁵)_(n)S(O)₂R¹⁰ where n is 1 or 2, and R¹⁴ R¹⁵ are H; R² isselected from H, F, Cl, Br, I, CN, CF₃, —NO₂, —C(═Y)R¹⁰, —C(═Y)OR¹⁰,—C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl; R³ is fused bicyclic C₄-C₂₀ heterocyclyl or fusedbicyclic C₁-C₂₀ heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached optionally form asaturated, partially unsaturated or fully unsaturated C₃-C₂₀heterocyclic ring optionally containing one or more additional ringatoms selected from N, O or S, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom oxo, (C₂)_(m)OR¹⁰, NR¹⁰R¹¹, CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰,NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹, C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl andC₁-C₂₀ heteroaryl; R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂alkyl, or —(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms towhich they are attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀,—NR¹²C(═Y)OR¹¹, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰,—OC(═Y)OR¹⁰, —OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹),—OP(OR¹⁰)(OR¹¹), SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰),—S(O)₂(OR¹⁰), —SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionallysubstituted alkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈optionally substituted alkynyl, C₃-C₁₂ optionally substitutedcarbocyclyl, C₂-C₂₀ optionally substituted heterocyclyl, C₆-C₂₀optionally substituted aryl, C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 5. The compound of claim 4 wherein R¹⁰ isC₁-C₁₂ alkyl or C₆-C₂₀ aryl.
 6. A compound selected from Formula Ia andFormula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is—(CR¹⁴R¹⁵)_(n)S(O)₂NR¹⁰R¹¹ where n is 1 or 2, and R¹⁴ and R¹⁵ are H; R²is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂, —C(═Y)R¹⁰, —C(═Y)OR¹⁰,—C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl; R³ is fused bicyclic C₄-C₂₀ heterocyclyl or fusedbicyclic C₁-C₂₀ heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached optionally form asaturated, partially unsaturated or fully unsaturated C₃-C₂₀heterocyclic ring optionally containing one or more additional ringatoms selected from N, O or S, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹, CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰,NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹, C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl andC₁-C₂₀ heteroaryl; R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂alkyl, or —(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms towhich they are attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, R¹⁶ and R¹⁷ are independently H, C₁-C₁₂ alkyl, C₂-C₈alkynyl, C₃-C₁₂ carbocyclyl, or C₆-C₂₀ aryl, R¹⁸ and R¹⁹ together withthe carbon to which they are attached form a C₃-C₂₀ heterocyclic ring,where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, and fused bicyclicC₁-C₂₀ heteroaryl are optionally substituted with one or more groupsindependently selected from F, Cl, Br, I, CN, CF₃, —NO₂, oxo, R¹⁰,—C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 7. A compound selected from Formula Ia andFormula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is —C(═Y)NR¹⁰R¹¹where Y is O and R¹⁰ and R¹¹ together with the nitrogen to which theyare attached form a C₂-C₂₀ heterocyclic ring; R² is selected from H, F,Cl, Br, I, CN, CF₃, —NO₂, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl; R³ is fused bicyclic C₄-C₂₀ heterocyclyl or fusedbicyclic C₁-C₂₀ heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached optionally form asaturated, partially unsaturated or fully unsaturated C₃-C₂₀heterocyclic ring optionally containing one or more additional ringatoms selected from N, O or S, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹, CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰,NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹, C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl andC₁-C₂₀ heteroaryl; R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂alkyl, or —(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms towhich they are attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 8. The compound of claim 7 wherein R¹⁰ and R¹¹together with the nitrogen to which they are attached form a C₂-C₂₀heterocyclic ring selected from morpholinyl, piperidinyl, piperazinyl,and pyrrolidinyl.
 9. A compound selected from Formula Ia and Formula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is —C(═Y)NR¹⁰R¹¹where Y is O and R¹⁰ and R¹¹ are independently selected from H andC₁-C₁₂ alkyl; R² is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂,—C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹,—NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰,—OC(═Y)R¹⁰, —OC(═Y)OR¹⁰, —OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰),—OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹), SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰), —SC(═Y)R¹⁰, —SC(═Y)OR¹⁰,—SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, and C₁-C₂₀ heteroaryl; R³is fused bicyclic C₄-C₂₀ heterocyclyl or fused bicyclic C₁-C₂₀heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ together with the nitrogen towhich they are attached optionally form a saturated, partiallyunsaturated or fully unsaturated C₃-C₂₀ heterocyclic ring optionallycontaining one or more additional ring atoms selected from N, O or S,wherein said heterocyclic ring is optionally substituted with one ormore groups independently selected from oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹,CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰, NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹,C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl and C₁-C₂₀ heteroaryl; R¹⁴and R¹⁵ are independently selected from H, C₁-C₁₂ alkyl, or—(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms to which theyare attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 10. A compound selected from Formula Ia andFormula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is —C(═Y)NR¹⁰R¹¹where Y is O and R¹⁰ and R¹¹ are independently selected from H, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, and C₁-C₂₀ heteroaryl; R²is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂, —C(═Y)R¹⁰, —C(═Y)OR¹⁰,—C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl; R³ is fused bicyclic C₄-C₂₀ heterocyclyl or fusedbicyclic C₁-C₂₀ heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached optionally form asaturated, partially unsaturated or fully unsaturated C₃-C₂₀heterocyclic ring optionally containing one or more additional ringatoms selected from N, O or S, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹, CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰,NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹, C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl andC₁-C₂₀ heteroaryl; R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂alkyl, or —(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms towhich they are attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 11. A compound selected from Formula Ia andFormula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is —NHR¹² where R¹²is C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀heteroaryl; R² is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂,—C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹,—NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰,—OC(═Y)R¹⁰, —OC(═Y)OR¹⁰, —OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰),—OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹), SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰), —SC(═Y)R¹⁰, —SC(═Y)OR¹⁰,—SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, and C₁-C₂₀ heteroaryl; R³is fused bicyclic C₄-C₂₀ heterocyclyl or fused bicyclic C₁-C₂₀heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ together with the nitrogen towhich they are attached optionally form a saturated, partiallyunsaturated or fully unsaturated C₃-C₂₀ heterocyclic ring optionallycontaining one or more additional ring atoms selected from N, O or S,wherein said heterocyclic ring is optionally substituted with one ormore groups independently selected from oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹,CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰, NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹,C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl and C₁-C₂₀ heteroaryl; R¹⁴and R¹⁵ are independently selected from H, C₁-C₁₂ alkyl, or—(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms to which theyare attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 12. The compound of claim 11 wherein R¹² isphenyl or 4-pyridyl.
 13. A compound selected from Formula Ia and FormulaIb:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is —NR¹²C(═Y)R¹¹where Y is O, R¹² is H or C₁-C₁₂ alkyl, and R¹¹ is C₁-C₁₂ alkyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl; R²is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂, —C(═Y)R¹⁰, —C(═Y)OR¹⁰,—C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl; R³ is fused bicyclic C₄-C₂₀ heterocyclyl or fusedbicyclic C₁-C₂₀ heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached optionally form asaturated, partially unsaturated or fully unsaturated C₃-C₂₀heterocyclic ring optionally containing one or more additional ringatoms selected from N, O or S, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹, CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰,NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹, C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl andC₁-C₂₀ heteroaryl; R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂alkyl, or —(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms towhich they are attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 14. The compound of claim 13 wherein R¹¹ isselected from methyl, ethyl, propyl, isopropyl, isobutyl,2,2-dimethylpropyl, and tert-butyl.
 15. The compound of claim 13 whereinR¹¹ is selected from cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.
 16. A compound selected from Formula Ia and Formula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is —NR¹²S(O)₂R¹⁰where R¹² is H or C₁-C₁₂ alkyl, and R¹⁰ is C₁-C₁₂ alkyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl; R²is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂, —C(═Y)R¹⁰, —C(═Y)OR¹⁰,—C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl; R³ is fused bicyclic C₄-C₂₀ heterocyclyl or fusedbicyclic C₁-C₂₀ heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached optionally form asaturated, partially unsaturated or fully unsaturated C₃-C₂₀heterocyclic ring optionally containing one or more additional ringatoms selected from N, O or S, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹, CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰,NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹, C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl andC₁-C₂₀ heteroaryl; R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂alkyl, or —(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms towhich they are attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 17. A compound selected from Formula Ia andFormula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is S(O)₂NR¹⁰ R¹¹where R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a C₂-C₂₀ heterocyclic ring selected from morpholinyl, piperazinyl,and pyrrolidinyl; R² is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂,—C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹,—NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰,—OC(═Y)R¹⁰, —OC(═Y)OR¹⁰, —OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰),—OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹), SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰), —SC(═Y)R¹⁰, —SC(═Y)OR¹⁰,—SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, and C₁-C₂₀ heteroaryl; R³is fused bicyclic C₄-C₂₀ heterocyclyl or fused bicyclic C₁-C₂₀heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ together with the nitrogen towhich they are attached optionally form a saturated, partiallyunsaturated or fully unsaturated C₃-C₂₀ heterocyclic ring optionallycontaining one or more additional ring atoms selected from N, O or S,wherein said heterocyclic ring is optionally substituted with one ormore groups independently selected from oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹,CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰, NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹,C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl and C₁-C₂₀ heteroaryl; R¹⁴and R¹⁵ are independently selected from H, C₁-C₁₂ alkyl, or—(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms to which theyare attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 18. A compound selected from Formula Ia andFormula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is S(O)₂NR¹⁰ R¹¹where R¹⁰ and R¹¹ are independently selected from H and C₁-C₁₂ alkyl; R²is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂, —C(═Y)R¹⁰, —C(═Y)OR¹⁰,—C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl; R³ is fused bicyclic C₄-C₂₀ heterocyclyl or fusedbicyclic C₁-C₂₀ heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached optionally form asaturated, partially unsaturated or fully unsaturated C₃-C₂₀heterocyclic ring optionally containing one or more additional ringatoms selected from N, O or S, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹, CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰,NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹, C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl andC₁-C₂₀ heteroaryl; R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂alkyl, or —(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms towhich they are attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 19. The compound of claim 18 wherein R¹⁰ andR¹¹ are independently selected from H, substituted ethyl, andsubstituted propyl.
 20. A compound selected from Formula Ia and FormulaIb:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is C₂-C₁₂ alkyl; R²is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂, —C(═Y)R¹⁰, —C(═Y)OR¹⁰,—C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl; R³ is fused bicyclic C₄-C₂₀ heterocyclyl or fusedbicyclic C₁-C₂₀ heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached optionally form asaturated, partially unsaturated or fully unsaturated C₃-C₂₀heterocyclic ring optionally containing one or more additional ringatoms selected from N, O or S, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹, CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰,NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹, C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl andC₁-C₂₀ heteroaryl; R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂alkyl, or —(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms towhich they are attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 21. A compound selected from Formula Ia andFormula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is C₂-C₈ alkenyl; R²is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂, —C(═Y)R¹⁰, —C(═Y)OR¹⁰,—C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl; R³ is fused bicyclic C₄-C₂₀ heterocyclyl or fusedbicyclic C₁-C₂₀ heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached optionally form asaturated, partially unsaturated or fully unsaturated C₃-C₂₀heterocyclic ring optionally containing one or more additional ringatoms selected from N, O or S, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹, CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰,NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹, C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl andC₁-C₂₀ heteroaryl; R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂alkyl, or —(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms towhich they are attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 22. A compound selected from Formula Ia andFormula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is C₂-C₈ alkenyl; R²is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂, —C(═Y)R¹⁰, —C(═Y)OR¹⁰,—C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl; R³ is fused bicyclic C₄-C₂₀ heterocyclyl or fusedbicyclic C₁-C₂₀ heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached optionally form asaturated, partially unsaturated or fully unsaturated C₃-C₂₀heterocyclic ring optionally containing one or more additional ringatoms selected from N, O or S, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹, CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰,NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹, C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl andC₁-C₂₀ heteroaryl; R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂alkyl, or —(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms towhich they are attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6 ; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 23. The compound of claim 22 wherein C₂-C₈alkynyl is substituted with C₂-C₂₀ heterocyclyl.
 24. The compound ofclaim 23 wherein C₂-C₂₀ heterocyclyl is selected from morpholinyl,piperidinyl, piperazinyl, and pyrrolidinyl.
 25. The compound of claim 22wherein R¹ is selected from the groups:


26. A compound selected from Formula Ia and Formula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is C₆-C₂₀ aryl; R² isselected from H, F, Cl, Br, I, CN, CF₃, —NO₂, —C(═Y)R¹⁰, —C(═Y)OR¹⁰,—C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl; R³ is fused bicyclic C₄-C₂₀ heterocyclyl or fusedbicyclic C₁-C₂₀ heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached optionally form asaturated, partially unsaturated or fully unsaturated C₃-C₂₀heterocyclic ring optionally containing one or more additional ringatoms selected from N, O or S, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹, CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰,NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹, C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl andC₁-C₂₀ heteroaryl; R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂alkyl, or —(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms towhich they are attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C_(2-C) ₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6 ; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 27. The compound of claim 26 wherein R¹ isoptionally substituted phenyl.
 28. The compound of claim 27 whereinphenyl is substituted with one or more groups selected fromN-methylcarboxamide, isopropylsulfonylamino, methylsulfonyl,2-hydroxy-2-methylpropanamide, 2-hydroxypropanamide, 2-methoxyacetamide,(propan-2-ol)sulfonyl, 2-amino-2-methylpropanamide, 2-aminoacetamide,2-hydroxyacetamide, methylsulfonylamino, 2-9dimethylamino)acetamide,amino, acetylamino, carboxamide, (4-methylsulfonylpiperazino)-1-methyl,(4-methylpiperazino)-1-methyl, hydroxymethyl, and methoxy.
 29. Acompound selected from Formula Ia and Formula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is C₃-C₁₂carbocyclyl; R² is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂,—C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹,—NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰,—OC(═Y)R¹⁰, —OC(═Y)OR¹⁰, —OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰),—OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹), SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰), —SC(═Y)R¹⁰, —SC(═Y)OR¹⁰,—SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, and C₁-C₂₀ heteroaryl; R³is fused bicyclic C₄-C₂₀ heterocyclyl or fused bicyclic C₁-C₂₀heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ together with the nitrogen towhich they are attached optionally form a saturated, partiallyunsaturated or fully unsaturated C₃-C₂₀ heterocyclic ring optionallycontaining one or more additional ring atoms selected from N, O or S,wherein said heterocyclic ring is optionally substituted with one ormore groups independently selected from oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹,CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰, NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹,C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl and C₁-C₂₀ heteroaryl; R¹⁴and R¹⁵ are independently selected from H, C₁-C₁₂ alkyl, or—(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms to which theyare attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C_(20-C) ₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6 ; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 30. A compound selected from Formula Ia andFormula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is C₂-C₂₀heterocyclyl; R² is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂,—C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹,—NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰,—OC(═Y)R¹⁰, —OC(═Y)OR¹⁰, —OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰),—OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹), SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰), —SC(═Y)R¹⁰, —SC(═Y)OR¹⁰,—SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, and C₁-C₂₀ heteroaryl; R³is fused bicyclic C₄-C₂₀ heterocyclyl or fused bicyclic C₁-C₂₀heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ together with the nitrogen towhich they are attached optionally form a saturated, partiallyunsaturated or fully unsaturated C₃-C₂₀ heterocyclic ring optionallycontaining one or more additional ring atoms selected from N, O or S,wherein said heterocyclic ring is optionally substituted with one ormore groups independently selected from oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹,CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰, NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹,C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl and C₁-C₂₀ heteroaryl; R¹⁴and R¹⁵ are independently selected from H, C₁-C₁₂ alkyl, or—(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms to which theyare attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6 ; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 31. A compound selected from Formula Ia andFormula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is C₁-C₂₀heterocyclyl; R² is selected from H, F, Cl, Br, I, CN, CF₃, —NO₂,—C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹,—NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰,—OC(═Y)R¹⁰, —OC(═Y)OR¹⁰, —OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰),—OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹), SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰), —SC(═Y)R¹⁰, —SC(═Y)OR¹⁰,—SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, and C₁-C₂₀ heteroaryl; R³is fused bicyclic C₄-C₂₀ heterocyclyl or fused bicyclic C₁-C₂₀heteroaryl; R¹⁰, R¹¹ and R¹² are independently H, C₁-C₁₂ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀aryl, or C₁-C₂₀ heteroaryl, or R¹⁰ and R¹¹ together with the nitrogen towhich they are attached optionally form a saturated, partiallyunsaturated or fully unsaturated C₃-C₂₀ heterocyclic ring optionallycontaining one or more additional ring atoms selected from N, O or S,wherein said heterocyclic ring is optionally substituted with one ormore groups independently selected from oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹,CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰, NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹,C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl and C₁-C₂₀ heteroaryl; R¹⁴and R¹⁵ are independently selected from H, C₁-C₁₂ alkyl, or—(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms to which theyare attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, andfused bicyclic C₁-C₂₀ heteroaryl are optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, CF₃, —NO₂,oxo, R¹⁰, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6 ; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 32. The compound of claim 31 wherein R¹ is2-pyridyl, 3-pyridyl, 4-pyridyl, or 5-pyrimidinyl.
 33. A compoundselected from Formula Ia and Formula Ib:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof, wherein: X is O or S; R¹ is selected from H,F, Cl, Br, I, CN, —CR¹⁴R¹⁵—NR¹⁶R¹⁷, —CR¹⁴R¹⁵—NHR¹⁰,—(CR¹⁴R¹⁵)_(t)NR¹⁰R¹¹, —C (R¹⁴R¹⁵)_(n)NR¹²C(═Y)R¹⁰, —(CR¹⁴R¹⁵)_(n)NR¹²S(O)₂R¹⁰, —(CR¹⁴R¹⁵)_(m)OR¹⁰, —(CR₁₄R¹⁵)_(n)S(O)²R¹⁰,—(CR¹⁴R¹⁵)_(n)S(O)₂NR¹⁰R¹¹, —C(OR¹⁰,)R¹¹R¹⁴, —C(R¹⁴)═CR¹⁸R¹⁹, —(═Y)R¹⁰,—C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —C(═Y)NR¹⁰OR¹⁰, —C(═O)NR¹²S(O)₂R¹⁰,—C(═O)NR¹²(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —NO₂, —NHR¹², —NR¹²C(═Y)R¹¹,—NR¹²C(═Y)OR¹¹, —NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²S(O)₂R¹⁰, —NR¹²SO₂NR¹⁰R¹¹,—S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, C₂-C₁₂ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₁₂ carbocycyclyl, C₂-C₂₀ heterocyclyl,C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl; R² is selected from H, F, Cl, Br, I,CN, CF₃, —NO₂, —C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(m)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)OR¹⁰,—CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, —NR¹²C(═Y)R¹⁰, —NR¹²C(═Y)OR¹⁰,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, andC₁-C₂₀ heteroaryl; R³ is selected from:

where the wavy line indicates the site of attachment; R¹⁰, R¹¹ and R¹²are independently H, C₁-C₁₂ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl, or C₁-C₂₀ heteroaryl, orR¹⁰ and R¹¹ together with the nitrogen to which they are attachedoptionally form a saturated, partially unsaturated or fully unsaturatedC₃-C₂₀ heterocyclic ring optionally containing one or more additionalring atoms selected from N, O or S, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom oxo, (CH₂)_(m)OR¹⁰, NR¹⁰R¹¹, CF₃, F, Cl, Br, I, SO₂R¹⁰, C(═O)R¹⁰,NR¹²C(═Y)R¹¹, NR¹²S(O)₂R¹¹, C(═Y)NR¹⁰R¹¹, C₁-C₁₂ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₆-C₂₀ aryl andC₁-C₂₀ heteroaryl; R¹⁴ and R¹⁵ are independently selected from H, C₁-C₁₂alkyl, or —(CH₂)_(n)-aryl, or R¹⁴ and R¹⁵ together with the atoms towhich they are attached form a saturated or partially unsaturated C₃-C₁₂carbocyclic ring, R¹⁶ and R¹⁷ are independently H, C₁-C₁₂ alkyl, C₂-C₈alkynyl, C₃-C₁₂ carbocyclyl, or C₆-C₂₀ aryl, R¹⁸ and R¹⁹ together withthe carbon to which they are attached form a C₃-C₂₀ heterocyclic ring,where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, fused bicyclic C₄-C₂₀ heterocyclyl, and fused bicyclicC₁-C₂₀ heteroaryl are optionally substituted with one or more groupsindependently selected from F, Cl, Br, I, CN, CF₃, —NO₂, oxo, R¹⁰,—C(═Y)R¹⁰, —C(═Y)OR¹⁰, —C(═Y)NR¹⁰R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹⁰R¹¹,—(CR¹⁴R¹⁵)_(n)OR¹⁰, —NR¹⁰R¹¹, —NR¹²C(═Y)R₁₀, —NR¹²C(═Y)OR¹¹,—NR¹²C(═Y)NR¹⁰R¹¹, —NR¹²SO₂R¹⁰, ═NR¹², OR¹⁰, —OC(═Y)R¹⁰, —OC(═Y)OR¹⁰,—OC(═Y)NR¹⁰R¹¹, —OS(O)₂(OR¹⁰), —OP(═Y)(OR¹⁰)(OR¹¹), —OP(OR¹⁰)(OR¹¹),SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —S(O)(OR¹⁰), —S(O)₂(OR¹⁰),—SC(═Y)R¹⁰, —SC(═Y)OR¹⁰, —SC(═Y)NR¹⁰R¹¹, C₁-C₁₂ optionally substitutedalkyl, C₂-C₈ optionally substituted alkenyl, C₂,-C₈ optionallysubstituted alkynyl, C₃-C₁₂ optionally substituted carbocyclyl, C₂-C₂₀optionally substituted heterocyclyl, C₆-C₂₀ optionally substituted aryl,C₁-C₂₀ optionally substituted heteroaryl,—(CR¹⁴R¹⁵)_(t)—NR¹²C(═O)(CR¹⁴R¹⁵)NR¹⁰R¹¹, and (CR¹⁴R¹⁵)_(t)—NR¹⁰R¹¹; Yis O, S, or NR¹²; m is 0, 1, 2, 3, 4, 5 or 6 ; n is 1, 2, 3, 4, 5 or 6;and t is 2, 3, 4, 5 or
 6. 34. A pharmaceutical composition comprised ofa compound of claim 2 and a pharmaceutically acceptable carrier.
 35. Thecomposition according to claim 34, further comprising a therapeuticagent selected from a chemotherapeutic agent, an anti-inflammatoryagent, an immunomodulatory agent, a neurotropic factor, an agent fortreating cardiovascular disease, an agent for treating liver disease, ananti-viral agent, an agent for treating blood disorders, an agent fortreating diabetes, or an agent for treating immunodeficiency disorders.36. A composition comprising a compound of claim 2 in an amount todetectably inhibit P13 kinase activity and a pharmaceutically acceptablecarrier, adjuvant, or vehicle.
 37. A kit comprising: (a) a firstpharmaceutical composition comprising a compound as defined in claim 2;(b) a second pharmaceutical composition that comprises a compound havinganti-hyperproliferative activity; and (c) instructions for thesimultaneous, sequential or separate administration of said first andsecond pharmaceutical compositions to a patient in need thereof; whereinsaid first and second pharmaceutical compositions are contained inseparate containers.
 38. A pharmaceutical composition comprised of acompound of claim 1 and a pharmaceutically acceptable carrier.
 39. Apharmaceutical composition comprised of a compound of claim 3 and apharmaceutically acceptable carrier.
 40. A pharmaceutical compositioncomprised of a compound of claim 4 and a pharmaceutically acceptablecarrier.
 41. A pharmaceutical composition comprised of a compound ofclaim 6 and a pharmaceutically acceptable carrier.
 42. A pharmaceuticalcomposition comprised of a compound of claim 7 and a pharmaceuticallyacceptable carrier.
 43. A pharmaceutical composition comprised of acompound of claim 9 and a pharmaceutically acceptable carrier.
 44. Apharmaceutical composition comprised of a compound of claim 10 and apharmaceutically acceptable carrier.
 45. A pharmaceutical compositioncomprised of a compound of claim 11 and a pharmaceutically acceptablecarrier.
 46. A pharmaceutical composition comprised of a compound ofclaim 13 and a pharmaceutically acceptable carrier.
 47. A pharmaceuticalcomposition comprised of a compound of claim 16 and a pharmaceuticallyacceptable carrier.
 48. A pharmaceutical composition comprised of acompound of claim 17 and a pharmaceutically acceptable carrier.
 49. Apharmaceutical composition comprised of a compound of claim 18 and apharmaceutically acceptable carrier.
 50. A pharmaceutical compositioncomprised of a compound of claim 20 and a pharmaceutically acceptablecarrier.
 51. A pharmaceutical composition comprised of a compound ofclaim 21 and a pharmaceutically acceptable carrier.
 52. A pharmaceuticalcomposition comprised of a compound of claim 22 and a pharmaceuticallyacceptable carrier.
 53. A pharmaceutical composition comprised of acompound of claim 26 and a pharmaceutically acceptable carrier.
 54. Apharmaceutical composition comprised of a compound of claim 29 and apharmaceutically acceptable carrier.
 55. A pharmaceutical compositioncomprised of a compound of claim 30 and a pharmaceutically acceptablecarrier.
 56. A pharmaceutical composition comprised of a compound ofclaim 31 and a pharmaceutically acceptable carrier.
 57. A pharmaceuticalcomposition comprised of a compound of claim 33 and a pharmaceuticallyacceptable carrier.